Immune consequences of kinase inhibitors in development, undergoing clinical trials and in current use in melanoma treatment

References

• Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364(26):2507-16
   PubMed Web of Science ®Google Scholar
• Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 2012;380(9839):358-65
   PubMed Web of Science ®Google Scholar
• Long GV, Trefzer U, Davies MA, et al. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol 2012;13(11):1087-95
   PubMed Web of Science ®Google Scholar
• Lau DK, Andrews MC, Turner N, et al. A single-centre experience of patients with metastatic melanoma enrolled in a dabrafenib named patient programme. Melanoma Res 2014;24(2):144-9
   PubMedGoogle Scholar
• Lito P, Rosen N, Solit DB. Tumor adaptation and resistance to RAF inhibitors. Nat Med 2013;19(11):1401-9
   PubMed Web of Science ®Google Scholar
• Sun C, Wang L, Huang S, et al. Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma. Nature 2014;508(7494):118-22
   PubMed Web of Science ®Google Scholar
• Solit DB, Rosen N. Towards a unified model of RAF inhibitor resistance. Cancer Discov 2014;4(1):27-30
   PubMedGoogle Scholar
• Cheng Y, Zhang G, Li G. Targeting MAPK pathway in melanoma therapy. Cancer Metastasis Rev 2013;32(3-4):567-84
   PubMed Web of Science ®Google Scholar
• Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 2012;367(2):107-14
   PubMed Web of Science ®Google Scholar
• Falchook GS, Lewis KD, Infante JR, et al. Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial. Lancet Oncol 2012;13(8):782-9
   PubMed Web of Science ®Google Scholar
• Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 2012;367(18):1694-703
   PubMed Web of Science ®Google Scholar
• Dabrafenib plus trametinib vs vemurafenib alone in unresectable or metastatic BRAF V600E/K cutaneous melanoma (COMBI-v). Available from: http://clinicaltrials.gov/ct2/show/NCT01597908
   Google Scholar
• coBRIM: a Phase 3 study comparing GDC-0973 (Cobimetinib), a MEK inhibitor, in combination with vemurafenib vs vemurafenib alone in patients with metastatic melanoma. Available from: www.clinicaltrials.gov/ct2/show/NCT01689519
   Google Scholar
• A study comparing trametinib and dabrafenib combination therapy to dabrafenib monotherapy in subjects with BRAF-mutant melanoma. Available from: http://clinicaltrials.gov/show/NCT01584648
   Google Scholar
• GlaxoSmithKline. GSK announces headline results for Phase III study of the combination of Tafinlar^® (dabrafenib) and Mekinist^® (trametinib) in metastatic melanoma. GlaxoSmithKline plc; London, United Kingdom: 2014
   Google Scholar
• McCubrey JA, Steelman LS, Kempf CR, et al. Therapeutic resistance resulting from mutations in Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR signaling pathways. J Cell Physiol 2011;226(11):2762-81
   PubMed Web of Science ®Google Scholar
• Hong DS, Bowles DW, Falchook GS, et al. A multicenter phase I trial of PX-866, an oral irreversible phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors. Clin Cancer Res 2012;18(15):4173-82
   PubMed Web of Science ®Google Scholar
• Shapiro GI, Rodon J, Bedell C, et al. Phase I safety, pharmacokinetic, and pharmacodynamic study of SAR245408 (XL147), an oral pan-class I PI3K inhibitor, in patients with advanced solid tumors. Clin Cancer Res 2014;20(1):233-45
   PubMed Web of Science ®Google Scholar
• Moreno Garcia V, Baird RD SK, Basu B, et al. A phase I study evaluating GDC-0941, an oral phosphoinositide-3 kinase (PI3K) inhibitor, in patients with advanced solid tumors or multiple myeloma ASCO. Chicago, IL, USA, 2011
   Google Scholar
• Rodon J, Brana I, Siu LL, et al. Phase I dose-escalation and -expansion study of buparlisib (BKM120), an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors. Invest New Drugs 2014. [Epub ahead of print]
   Google Scholar
• A study of ZSTK474 in Japanese patients with advanced solid malignancies. Available from: http://clinicaltrials.gov/show/NCT01682473
   Google Scholar
• Papadopoulos K, Tabernero J, Markman B, et al. Phase I safety, pharmacokinetic and pharmacodynamic study of SAR245409 (XL765), a novel, orally administered PI3K/mTOR inhibitor in patients with advanced solid tumors. Clin Cancer Res 2014;20(9):2445-56
   PubMedGoogle Scholar
• Mahadevan D, Chiorean EG, Harris WB, et al. Phase I pharmacokinetic and pharmacodynamic study of the pan-PI3K/mTORC vascular targeted pro-drug SF1126 in patients with advanced solid tumours and B-cell malignancies. Eur J Cancer 2012;48(18):3319-27
   PubMed Web of Science ®Google Scholar
• Britten CD. PI3K and MEK inhibitor combinations: examining the evidence in selected tumor types. Cancer Chemother Pharmacol 2013;71(6):1395-409
   PubMed Web of Science ®Google Scholar
• Study to investigate the safety, pharmacokinetics, pharmacodynamics, and clinical activity of GSK2126458 and GSK1120212 combination therapy in subjects with advanced solid tumors. Available from: http://clinicaltrials.gov/show/NCT01248858
   Google Scholar
• Study of PI3 kinase/mTOR inhibitor BEZ235 twice daily for advanced solid tumors. Available from: http://clinicaltrials.gov/show/NCT01343498
   Google Scholar
• A Study of BEZ235 in adult Japanese patients with advanced solid tumors. Available from: http://clinicaltrials.gov/show/NCT01195376
   Google Scholar
• A Study evaluating GDC-0980 administered once weekly in patients with refractory solid tumors or non-Hodgkin’s lymphoma. Available from: http://clinicaltrials.gov/ct2/show/NCT00854126
   Google Scholar
• Study of PF-05212384 (Also Known as PKI-587) administered intravenously to subjects with solid tumors (B2151001). Available from: https://clinicaltrials.gov/ct2/show/NCT00940498
   Google Scholar
• Bellmunt J, Szczylik C, Feingold J, et al. Temsirolimus safety profile and management of toxic effects in patients with advanced renal cell carcinoma and poor prognostic features. Ann Oncol 2008;19(8):1387-92
   PubMed Web of Science ®Google Scholar
• Vemurafenib in combination with everolimus or temsirolimus with advanced cancer. Available from: http://clinicaltrials.gov/ct2/show/NCT01596140
   Google Scholar
• Naing A, Aghajanian C, Raymond E, et al. Safety, tolerability, pharmacokinetics and pharmacodynamics of AZD8055 in advanced solid tumours and lymphoma. Br J Cancer 2012;107(7):1093-9
   PubMed Web of Science ®Google Scholar
• Study of oral OSI-027 in patients with advanced solid tumors or lymphoma. Available from: http://clinicaltrials.gov/show/NCT00698243
   Google Scholar
• Study to assess safety, pharmacokinetics, and efficacy of oral CC-223 for patients with advanced solid tumors, non-Hodgkin lymphoma or multiple myeloma. Available from: http://clinicaltrials.gov/show/NCT01177397
   Google Scholar
• Gajate C, Mollinedo F. Edelfosine and perifosine induce selective apoptosis in multiple myeloma by recruitment of death receptors and downstream signaling molecules into lipid rafts. Blood 2007;109(2):711-19
   PubMed Web of Science ®Google Scholar
• Ernst DS, Eisenhauer E, Wainman N, et al. Phase II study of perifosine in previously untreated patients with metastatic melanoma. Invest New Drugs 2005;23(6):569-75
   PubMedGoogle Scholar
• Garrett CR, Coppola D, Wenham RM, et al. Phase I pharmacokinetic and pharmacodynamic study of triciribine phosphate monohydrate, a small-molecule inhibitor of AKT phosphorylation, in adult subjects with solid tumors containing activated AKT. Invest New Drugs 2011;29(6):1381-9
   PubMed Web of Science ®Google Scholar
• Davies BR, Greenwood H, Dudley P, et al. Preclinical pharmacology of AZD5363, an inhibitor of AKT: pharmacodynamics, antitumor activity, and correlation of monotherapy activity with genetic background. Mol Cancer Ther 2012;11:873-87
   PubMed Web of Science ®Google Scholar
• Lin J, Sampath D, Nannini MA, et al. Targeting activated Akt with GDC-0068, a novel selective Akt inhibitor that is efficacious in multiple tumor models. Clin Cancer Res 2013;19:1760-72
   PubMed Web of Science ®Google Scholar
• Yap TA, Yan L, Patnaik A, et al. First-in-man clinical trial of the oral pan-AKT inhibitor MK-2206 in patients with advanced solid tumors. J Clin Oncol 2011;29(35):4688-95
   PubMed Web of Science ®Google Scholar
• A study evaluating the safety and tolerability of GDC-0068 in patients with refractory solid tumors. Available from: http://clinicaltrials.gov/show/NCT01090960
   Google Scholar
• Safety and pharmacology Of GDC-0068 in combination with docetaxel, fluoropyrimidine plus oxaliplatin, paclitaxel, or enzalutamide in patients with advanced solid tumors. Available from: http://clinicaltrials.gov/ct2/show/NCT01362374
   Google Scholar
• A study of the safety and activity of the MEK inhibitor given together with the AKT inhibitor to patients with multiple myeloma or solid tumor cancers. Available from: http://clinicaltrials.gov/show/NCT01476137
   Google Scholar
• Safety, tolerability & potential anti-cancer activity of increasing doses of AZD5363 in different treatment schedules. Available from: http://clinicaltrials.gov/show/NCT01226316
   Google Scholar
• Kwong LN, Davies MA. Targeted therapy for melanoma: rational combinatorial approaches. Oncogene 2014;33(1):1-9
   PubMed Web of Science ®Google Scholar
• Ribas A, Hodi FS, Callahan M, et al. Hepatotoxicity with combination of vemurafenib and ipilimumab. N Engl J Med 2013;368(14):1365-6
   PubMed Web of Science ®Google Scholar
• Boni A, Cogdill AP, Dang P, et al. Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function. Cancer Res 2010;70(13):5213-19
   PubMed Web of Science ®Google Scholar
• Comin-Anduix B, Chodon T, Sazegar H, et al. The oncogenic BRAF kinase inhibitor PLX4032/RG7204 does not affect the viability or function of human lymphocytes across a wide range of concentrations. Clin Cancer Res 2010;16(24):6040-8
   PubMed Web of Science ®Google Scholar
• Donia M, Fagone P, Nicoletti F, et al. BRAF inhibition improves tumor recognition by the immune system: potential implications for combinatorial therapies against melanoma involving adoptive T-cell transfer. Oncoimmunology 2012;1(9):1476-83
   PubMed Web of Science ®Google Scholar
• Du J, Miller AJ, Widlund HR, et al. MLANA/MART1 and SILV/PMEL17/GP100 are transcriptionally regulated by MITF in melanocytes and melanoma. Am J Pathol 2003;163(1):333-43
   PubMed Web of Science ®Google Scholar
• Wellbrock C, Marais R. Elevated expression of MITF counteracts B-RAF-stimulated melanocyte and melanoma cell proliferation. J Cell Biol 2005;170(5):703-8
   PubMedGoogle Scholar
• Wellbrock C, Rana S, Paterson H, et al. Oncogenic BRAF regulates melanoma proliferation through the lineage specific factor MITF. PLoS One 2008;3(7):e2734
   PubMed Web of Science ®Google Scholar
• Kono M, Dunn IS, Durda PJ, et al. Role of the mitogen-activated protein kinase signaling pathway in the regulation of human melanocytic antigen expression. Mol Cancer Res 2006;4(10):779-92
   PubMed Web of Science ®Google Scholar
• Wilmott JS, Long GV, Howle JR, et al. Selective BRAF inhibitors induce marked T-cell infiltration into human metastatic melanoma. Clin Cancer Res 2012;18(5):1386-94
   PubMed Web of Science ®Google Scholar
• Hong DS, Vence L, Falchook G, et al. BRAF(V600) inhibitor GSK2118436 targeted inhibition of mutant BRAF in cancer patients does not impair overall immune competency. Clin Cancer Res 2012;18(8):2326-35
   PubMedGoogle Scholar
• Frederick DT, Piris A, Cogdill AP, et al. BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma. Clin Cancer Res 2013;19(5):1225-31
   PubMed Web of Science ®Google Scholar
• Kortum RL, Rouquette-Jazdanian AK, Samelson LE. Ras and extracellular signal-regulated kinase signaling in thymocytes and T cells. Trends Immunol 2013;34(6):259-68
   PubMed Web of Science ®Google Scholar
• Su F, Viros A, Milagre C, et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med 2012;366(3):207-15
   PubMed Web of Science ®Google Scholar
• Robert C, Arnault JP, Mateus C. RAF inhibition and induction of cutaneous squamous cell carcinoma. Curr Opin Oncol 2011;23(2):177-82
   PubMed Web of Science ®Google Scholar
• Oberholzer PA, Kee D, Dziunycz P, et al. RAS mutations are associated with the development of cutaneous squamous cell tumors in patients treated with RAF inhibitors. J Clin Oncol 2012;30(3):316-21
   PubMed Web of Science ®Google Scholar
• Sanchez-Laorden B, Viros A, Girotti MR, et al. BRAF inhibitors induce metastasis in RAS mutant or inhibitor-resistant melanoma cells by reactivating MEK and ERK signaling. Sci Signal 2014;7(318):ra30
   PubMed Web of Science ®Google Scholar
• Vella LJ, Pasam A, Dimopoulos N, et al. MEK inhibition, alone or in combination with BRAF inhibition, affects multiple functions of isolated normal human lymphocytes and dendritic cells. Cancer Immunol Res 2014;2(4):351-60
   PubMed Web of Science ®Google Scholar
• Vosganian GS, Bos R, Sherman LA. Immunologic effects of an orally available BRAFV600E inhibitor in BRAF wild-type murine models. J Immunother 2012;35(6):473-7
   PubMedGoogle Scholar
• Callahan MK, Masters G, Pratilas CA, et al. Paradoxical activation of T cells via augmented ERK signaling mediated by a RAF inhibitor. Cancer Immunol Res 2014;2:1
   PubMed Web of Science ®Google Scholar
• Schilling B, Sondermann W, Zhao F, et al. Differential influence of vemurafenib and dabrafenib on patients’ lymphocytes despite similar clinical efficacy in melanoma. Ann Oncol 2014;25(3):747-53
   PubMed Web of Science ®Google Scholar
• Cooper ZA, Frederick DT, Juneja VR, et al. BRAF inhibition is associated with increased clonality in tumor-infiltrating lymphocytes. Oncoimmunology 2013;2(10):e26615
   PubMedGoogle Scholar
• Knight DA, Ngiow SF, Li M, et al. Host immunity contributes to the anti-melanoma activity of BRAF inhibitors. J Clin Invest 2013;123(3):1371-81
   PubMed Web of Science ®Google Scholar
• Ho PC, Meeth KM, Tsui YC, et al. Immune-based antitumor effects of BRAF Inhibitors rely on signaling by CD40L and IFN-gamma. Cancer Res 2014. [Epub ahead of print]
   Google Scholar
• Yang L, DeBusk LM, Fukuda K, et al. Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell 2004;6(4):409-21
   PubMed Web of Science ®Google Scholar
• Lindau D, Gielen P, Kroesen M, et al. The immunosuppressive tumour network: myeloid-derived suppressor cells, regulatory T cells and natural killer T cells. Immunology 2013;138(2):105-15
   PubMed Web of Science ®Google Scholar
• Schilling B, Sucker A, Griewank K, et al. Vemurafenib reverses immunosuppression by myeloid derived suppressor cells. Int J Cancer 2013;133(7):1653-63
   PubMed Web of Science ®Google Scholar
• Schilling B, Paschen A. Immunological consequences of selective BRAF inhibitors in malignant melanoma: neutralization of myeloid-derived suppressor cells. Oncoimmunology 2013;2(8):e25218
   PubMed Web of Science ®Google Scholar
• Wilmott JS, Haydu LE, Menzies AM, et al. Dynamics of chemokine, cytokine, and growth factor serum levels in braf-mutant melanoma patients during BRAF inhibitor treatment. J Immunol 2014;192(5):2505-13
   PubMed Web of Science ®Google Scholar
• Gray-Schopfer VC, Karasarides M, Hayward R, Marais R. Tumor necrosis factor-alpha blocks apoptosis in melanoma cells when BRAF signaling is inhibited. Cancer Res 2007;67(1):122-9
   PubMed Web of Science ®Google Scholar
• Sapkota B, Hill CE, Pollack BP. Vemurafenib enhances MHC induction in BRAF homozygous melanoma cells. Oncoimmunology 2013;2(1):e22890
   PubMed Web of Science ®Google Scholar
• Khalili JS, Liu S, Rodriguez-Cruz TG, et al. Oncogenic BRAF(V600E) promotes stromal cell-mediated immunosuppression via induction of interleukin-1 in melanoma. Clin Cancer Res 2012;18(19):5329-40
   PubMed Web of Science ®Google Scholar
• Liu C, Peng W, Xu C, et al. BRAF inhibition increases tumor infiltration by T cells and enhances the antitumor activity of adoptive immunotherapy in mice. Clin Cancer Res 2013;19(2):393-403
   PubMed Web of Science ®Google Scholar
• Hooijkaas A, Gadiot J, Morrow M, et al. Selective BRAF inhibition decreases tumor-resident lymphocyte frequencies in a mouse model of human melanoma. Oncoimmunology 2012;1(5):609-17
   PubMed Web of Science ®Google Scholar
• Koya RC, Mok S, Otte N, et al. BRAF inhibitor vemurafenib improves the antitumor activity of adoptive cell immunotherapy. Cancer Res 2012;72(16):3928-37
   PubMed Web of Science ®Google Scholar
• Ackerman A, Klein O, McDermott DF, et al. Outcomes of patients with metastatic melanoma treated with immunotherapy prior to or after BRAF inhibitors. Cancer 2014;120(11):1695-701
   PubMed Web of Science ®Google Scholar
• Johnson DB, Wallender EK, Cohen DN, et al. Severe cutaneous and neurologic toxicity in melanoma patients during vemurafenib administration following anti-PD-1 therapy. Cancer Immunol Res 2013;1:373
   PubMedGoogle Scholar
• Ipilimumab with or without dabrafenib, and/or trametinib in treating patients with melanoma that is metastatic or cannot be removed by surgery. Available from: http://therapy.collabrx.com/melanoma/trial/NCT01940809
   Google Scholar
• Study of dabrafenib +/- trametinib in combination with ipilimumab for v600e/k mutation positive metastatic or unresectable melanoma. Available from: http://clinicaltrials.gov/ct2/show/NCT01767454
   Google Scholar
• Phase II safety study of vemurafenib followed by ipilimumab in subjects With V600 BRAF mutated advanced melanoma. Available from: http://clinicaltrials.gov/show/NCT01673854
   Google Scholar
• Ph I ipilimumab vemurafenib combo in patients with v-raf murine sarcoma viral oncogene homolog B1 (BRAF). Available from: http://clinicaltrials.gov/ct2/show/NCT01400451
   Google Scholar
• A phase 1b study of MPDL3280A (an engineered anti-PDL1 antibody) in combination with vemurafinib (Zelboraf®) in patients with previously untreated BRAFV600-mutation positive metastatic melanoma. Available from: http://clinicaltrials.gov/ct2/show/NCT01656642
   Google Scholar
• Phase 1 safety and tolerability of medi4736 in combination with Dabrafenib and Trametinib or With Trametinib Alone. Available from: http://clinicaltrials.gov/show/NCT02027961
   Google Scholar
• Dumont FJ, Staruch MJ, Fischer P, et al. Inhibition of T cell activation by pharmacologic disruption of the MEK1/ERK MAP kinase or calcineurin signaling pathways results in differential modulation of cytokine production. J Immunol 1998;160(6):2579-89
   PubMedGoogle Scholar
• Li YQ, Hii CS, Costabile M, et al. Regulation of lymphotoxin production by the p21ras-raf-MEK-ERK cascade in PHA/PMA-stimulated Jurkat cells. J Immunol 1999;162(6):3316-20
   PubMedGoogle Scholar
• Yamaguchi T, Kakefuda R, Tanimoto A, et al. Suppressive effect of an orally active MEK1/2 inhibitor in two different animal models for rheumatoid arthritis: a comparison with leflunomide. Inflamm Res 2012;61(5):445-54
   PubMedGoogle Scholar
• Shindo T, Kim TK, Benjamin CL, et al. MEK inhibitors selectively suppress alloreactivity and graft-versus-host disease in a memory stage-dependent manner. Blood 2013;121(23):4617-26
   PubMedGoogle Scholar
• Berthon C, Driss V, Liu J, et al. In acute myeloid leukemia, B7-H1 (PD-L1) protection of blasts from cytotoxic T cells is induced by TLR ligands and interferon-gamma and can be reversed using MEK inhibitors. Cancer Immunol Immunother 2010;59(12):1839-49
   PubMed Web of Science ®Google Scholar
• Yamamoto R, Nishikori M, Tashima M, et al. B7-H1 expression is regulated by MEK/ERK signaling pathway in anaplastic large cell lymphoma and Hodgkin lymphoma. Cancer Sci 2009;100(11):2093-100
   PubMed Web of Science ®Google Scholar
• Jiang X, Zhou J, Giobbie-Hurder A, et al. The Activation of MAPK in melanoma cells resistant to BRAF inhibition promotes PD-L1 expression that is reversible by MEK and PI3K inhibition. Clin Cancer Res 2013;19(3):598-609
   PubMed Web of Science ®Google Scholar
• Wong H, Vernillet L, Peterson A, et al. Bridging the gap between preclinical and clinical studies using pharmacokinetic-pharmacodynamic modeling: an analysis of GDC-0973, a MEK inhibitor. Clin Cancer Res 2012;18(11):3090-9
   PubMed Web of Science ®Google Scholar
• Leijen S, Middleton MR, Tresca P, et al. Phase I dose-escalation study of the safety, pharmacokinetics, and pharmacodynamics of the MEK inhibitor RO4987655 (CH4987655) in patients with advanced solid tumors. Clin Cancer Res 2012;18(17):4794-805
   PubMed Web of Science ®Google Scholar
• Aguilera-Montilla N, Chamorro S, Nieto C, et al. Aryl hydrocarbon receptor contributes to the MEK/ERK-dependent maintenance of the immature state of human dendritic cells. Blood 2013;121(15):e108-17
   Google Scholar
• Nakahara T, Moroi Y, Uchi H, Furue M. Differential role of MAPK signaling in human dendritic cell maturation and Th1/Th2 engagement. J Dermatol Sci 2006;42(1):1-11
   PubMed Web of Science ®Google Scholar
• Puig-Kroger A, Relloso M, Fernandez-Capetillo O, et al. Extracellular signal-regulated protein kinase signaling pathway negatively regulates the phenotypic and functional maturation of monocyte-derived human dendritic cells. Blood 2001;98(7):2175-82
   PubMedGoogle Scholar
• Ott PA, Henry T, Baranda SJ, et al. Inhibition of both BRAF and MEK in BRAF(V600E) mutant melanoma restores compromised dendritic cell (DC) function while having differential direct effects on DC properties. Cancer Immunol Immunother 2013;62(4):811-22
   PubMed Web of Science ®Google Scholar
• Arrighi JF, Rebsamen M, Rousset F, et al. A critical role for p38 mitogen-activated protein kinase in the maturation of human blood-derived dendritic cells induced by lipopolysaccharide, TNF-alpha, and contact sensitizers. J Immunol 2001;166(6):3837-45
   PubMedGoogle Scholar
• Morris EJ, Jha S, Restaino CR, et al. Discovery of a novel ERK inhibitor with activity in models of acquired resistance to BRAF and MEK inhibitors. Cancer Discov 2013;3(7):742-50
   PubMed Web of Science ®Google Scholar
• Sheppard KE, McArthur GA. The cell-cycle regulator CDK4: an emerging therapeutic target in melanoma. Clin Cancer Res 2013;19(19):5320-8
   PubMed Web of Science ®Google Scholar
• Young RJ, Waldeck K, Martin C, et al. Loss of CDKN2A expression is a frequent event in primary invasive melanoma and correlates with sensitivity to the CDK4/6 inhibitor PD0332991 in melanoma cell lines. Pigment Cell Melanoma Res 2014. [Epub ahead of print]
   PubMed Web of Science ®Google Scholar
• LGX818 in combination with agents (MEK162; BKM120; LEE011; BGJ398; INC280) in advanced BRAF melanoma (LOGIC). Available from: http://clinicaltrials.gov/show/NCT01820364
   Google Scholar
• Dinaciclib in treating patients with stage III-IV melanoma. Available from: http://clinicaltrials.gov/show/NCT01026324
   Google Scholar
• Dinaciclib in treating patients with stage IV melanoma. Available from: http://clinicaltrials.gov/show/NCT00937937
   Google Scholar
• A Phase 1 study of LY2835219 in participants with advanced cancer. Available from: http://clinicaltrials.gov/show/NCT01394016
   Google Scholar
• Vanden Bush TJ, Bishop GA. CDK-mediated regulation of cell functions via c-Jun phosphorylation and AP-1 activation. PLoS One 2011;6(4):e19468
   Google Scholar
• Liu L, Schwartz B, Tsubota Y, et al. Cyclin-dependent kinase inhibitors block leukocyte adhesion and migration. J Immunol 2008;180(3):1808-17
   PubMed Web of Science ®Google Scholar
• Fattore L, Marra E, Pisanu ME, et al. Activation of an early feedback survival loop involving phospho-ErbB3 is a general response of melanoma cells to RAF/MEK inhibition and is abrogated by anti-ErbB3 antibodies. J Transl Med 2013;11:180
   PubMed Web of Science ®Google Scholar
• Nazarian R, Shi H, Wang Q, et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 2010;468(7326):973-7
   PubMed Web of Science ®Google Scholar
• Girotti MR, Pedersen M, Sanchez-Laorden B, et al. Inhibiting EGF receptor or SRC family kinase signaling overcomes BRAF inhibitor resistance in melanoma. Cancer Discov 2013;3(2):158-67
   PubMed Web of Science ®Google Scholar
• Stehle F, Schulz K, Fahldieck C, et al. Reduced immunosuppressive properties of axitinib in comparison with other tyrosine kinase inhibitors. J Biol Chem 2013;288(23):16334-47
   PubMed Web of Science ®Google Scholar
• Houben R, Voigt H, Noelke C, et al. MAPK-independent impairment of T-cell responses by the multikinase inhibitor sorafenib. Mol Cancer Ther 2009;8(2):433-40
   PubMed Web of Science ®Google Scholar
• Florcken A, Takvorian A, Van Lessen A, et al. Sorafenib, but not sunitinib, induces regulatory T cells in the peripheral blood of patients with metastatic renal cell carcinoma. Anticancer Drugs 2012;23(3):298-302
   PubMedGoogle Scholar
• Chen ML, Yan BS, Lu WC, et al. Sorafenib relieves cell-intrinsic and cell-extrinsic inhibitions of effector T cells in tumor microenvironment to augment antitumor immunity. Int J Cancer 2014;134(2):319-31
   PubMed Web of Science ®Google Scholar
• Ozao-Choy J, Ma G, Kao J, et al. The novel role of tyrosine kinase inhibitor in the reversal of immune suppression and modulation of tumor microenvironment for immune-based cancer therapies. Cancer Res 2009;69(6):2514-22
   PubMed Web of Science ®Google Scholar
• Finke JH, Rini B, Ireland J, et al. Sunitinib reverses type-1 immune suppression and decreases T-regulatory cells in renal cell carcinoma patients. Clin Cancer Res 2008;14(20):6674-82
   PubMed Web of Science ®Google Scholar
• Ko JS, Zea AH, Rini BI, et al. Sunitinib mediates reversal of myeloid-derived suppressor cell accumulation in renal cell carcinoma patients. Clin Cancer Res 2009;15(6):2148-57
   PubMed Web of Science ®Google Scholar
• Farsaci B, Higgins JP, Hodge JW. Consequence of dose scheduling of sunitinib on host immune response elements and vaccine combination therapy. Int J Cancer 2012;130(8):1948-59
   PubMed Web of Science ®Google Scholar
• Gu Y, Zhao W, Meng F, et al. Sunitinib impairs the proliferation and function of human peripheral T cell and prevents T-cell-mediated immune response in mice. Clin Immunol 2010;135(1):55-62
   PubMedGoogle Scholar
• Jaini R, Rayman P, Cohen PA, et al. Combination of sunitinib with anti-tumor vaccination inhibits T cell priming and requires careful scheduling to achieve productive immunotherapy. Int J Cancer 2014;134(7):1695-705
   PubMedGoogle Scholar
• Zhang X, Fang X, Gao Z, et al. Axitinib, a selective inhibitor of vascular endothelial growth factor receptor, exerts an anticancer effect in melanoma through promoting antitumor immunity. Anticancer Drugs 2014;25(2):204-11
   PubMed Web of Science ®Google Scholar
• Bose A, Lowe DB, Rao A, Storkus WJ. Combined vaccine + axitinib therapy yields superior antitumor efficacy in a murine melanoma model. Melanoma Res 2012;22(3):236-43
   PubMedGoogle Scholar
• Ipilimumab and imatinib mesylate in advanced cancer. Available from: http://clinicaltrials.gov/ct2/show/NCT01738139
   Google Scholar
• Larmonier N, Janikashvili N, LaCasse CJ, et al. Imatinib mesylate inhibits CD4+ CD25+ regulatory T cell activity and enhances active immunotherapy against BCR-ABL- tumors. J Immunol 2008;181(10):6955-63
   PubMed Web of Science ®Google Scholar
• Balachandran VP, Cavnar MJ, Zeng S, et al. Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido. Nat Med 2011;17(9):1094-100
   PubMed Web of Science ®Google Scholar
• Borg C, Terme M, Taieb J, et al. Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell-dependent antitumor effects. J Clin Invest 2004;114(3):379-88
   PubMed Web of Science ®Google Scholar
• Menard C, Blay JY, Borg C, et al. Natural killer cell IFN-gamma levels predict long-term survival with imatinib mesylate therapy in gastrointestinal stromal tumor-bearing patients. Cancer Res 2009;69(8):3563-9
   PubMed Web of Science ®Google Scholar
• Appel S, Balabanov S, Brummendorf TH, Brossart P. Effects of imatinib on normal hematopoiesis and immune activation. Stem Cells 2005;23(8):1082-8
   PubMedGoogle Scholar
• Taieb J, Maruyama K, Borg C, et al. Imatinib mesylate impairs Flt3L-mediated dendritic cell expansion and antitumor effects in vivo. Blood 2004;103(5):1966-7. author reply 67
   PubMedGoogle Scholar
• Seggewiss R, Lore K, Greiner E, et al. Imatinib inhibits T-cell receptor-mediated T-cell proliferation and activation in a dose-dependent manner. Blood 2005;105(6):2473-9
   PubMed Web of Science ®Google Scholar
• Fei F, Yu Y, Schmitt A, et al. Dasatinib exerts an immunosuppressive effect on CD8+ T cells specific for viral and leukemia antigens. Exp Hematol 2008;36(10):1297-308
   PubMedGoogle Scholar
• Schade AE, Schieven GL, Townsend R, et al. Dasatinib, a small-molecule protein tyrosine kinase inhibitor, inhibits T-cell activation and proliferation. Blood 2008;111(3):1366-77
   PubMed Web of Science ®Google Scholar
• Blake S, Hughes TP, Mayrhofer G, Lyons AB. The Src/ABL kinase inhibitor dasatinib (BMS-354825) inhibits function of normal human T-lymphocytes in vitro. Clin Immunol 2008;127(3):330-9
   PubMedGoogle Scholar
• Mustjoki S, Ekblom M, Arstila TP, et al. Clonal expansion of T/NK-cells during tyrosine kinase inhibitor dasatinib therapy. Leukemia 2009;23(8):1398-405
   PubMed Web of Science ®Google Scholar
• Sillaber C, Herrmann H, Bennett K, et al. Immunosuppression and atypical infections in CML patients treated with dasatinib at 140 mg daily. Eur J Clin Invest 2009;39(12):1098-109
   PubMed Web of Science ®Google Scholar
• Yang Y, Liu C, Peng W, et al. Antitumor T-cell responses contribute to the effects of dasatinib on c-KIT mutant murine mastocytoma and are potentiated by anti-OX40. Blood 2012;120(23):4533-43
   PubMedGoogle Scholar
• Qian BZ, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell 2010;141(1):39-51
   PubMed Web of Science ®Google Scholar
• DeNardo DG, Brennan DJ, Rexhepaj E, et al. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov 2011;1(1):54-67
   PubMed Web of Science ®Google Scholar
• Mitchem JB, Brennan DJ, Knolhoff BL, et al. Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses. Cancer Res 2013;73(3):1128-41
   PubMed Web of Science ®Google Scholar
• Mok S, Koya RC, Tsui C, et al. Inhibition of CSF-1 receptor improves the antitumor efficacy of adoptive cell transfer immunotherapy. Cancer Res 2014;74(1):153-61
   PubMed Web of Science ®Google Scholar
• A Phase 1b open label, dose escalation study of PLX3397 in combination with vemurafenib in V600-mutated BRAF melanoma. Available from: http://clinicaltrial.gov/ct2/show/NCT01826448
   Google Scholar
• Cabozantinib-S-Malate and Vemurafenib in treating patients with solid tumors or melanoma that is metastatic or that cannot be removed by surgery. Available from: http://clinicaltrials.gov/ct2/show/NCT01835184
   Google Scholar
• Cediranib Maleate and Selumetinib in treating patients with solid malignancies. Available from: http://clinicaltrials.gov/ct2/show/NCT01364051
   Google Scholar
• Glen H, Mason S, Patel H, et al. E7080, a multi-targeted tyrosine kinase inhibitor suppresses tumor cell migration and invasion. BMC Cancer 2011;11:309
   PubMed Web of Science ®Google Scholar
• An Open-Label, 2-Cohort, Multicenter, study of E7080 in previously treated subjects with unresectable stage III or stage IV melanoma. Available from: http://clinicaltrials.gov/show/NCT01136967
   Google Scholar
• Hannesdottir L, Tymoszuk P, Parajuli N, et al. Lapatinib and doxorubicin enhance the Stat1-dependent antitumor immune response. Eur J Immunol 2013;43(10):2718-29
   PubMed Web of Science ®Google Scholar
• Morse MA, Wei J, Hartman Z, et al. Synergism from combined immunologic and pharmacologic inhibition of HER2 in vivo. Int J Cancer 2010;126(12):2893-903
   PubMedGoogle Scholar
• Hamilton E, Blackwell K, Hobeika AC, et al. Phase 1 clinical trial of HER2-specific immunotherapy with concomitant HER2 kinase inhibition [corrected]. J Transl Med 2012;10:28
   PubMed Web of Science ®Google Scholar
• Albrecht H. Concurrent HER2 vaccination and inhibition of kinase activity: safety and immunogenicity. Immunotherapy 2012;4(7):671-4
   PubMedGoogle Scholar
• Pallis AG, Syrigos KN. Epidermal growth factor receptor tyrosine kinase inhibitors in the treatment of NSCLC. Lung Cancer 2013;80(2):120-30
   PubMed Web of Science ®Google Scholar
• Pivarcsi A, Muller A, Hippe A, et al. Tumor immune escape by the loss of homeostatic chemokine expression. Proc Natl Acad Sci USA 2007;104(48):19055-60
   PubMed Web of Science ®Google Scholar
• Pollack BP, Sapkota B, Cartee TV. Epidermal growth factor receptor inhibition augments the expression of MHC class I and II genes. Clin Cancer Res 2011;17(13):4400-13
   PubMed Web of Science ®Google Scholar
• Perez-Soler R, Delord JP, Halpern A, et al. HER1/EGFR inhibitor-associated rash: future directions for management and investigation outcomes from the HER1/EGFR inhibitor rash management forum. Oncologist 2005;10(5):345-56
   PubMed Web of Science ®Google Scholar
• Luo Q, Gu Y, Zheng W, et al. Erlotinib inhibits T-cell-mediated immune response via down-regulation of the c-Raf/ERK cascade and Akt signaling pathway. Toxicol Appl Pharmacol 2011;251(2):130-6
   PubMedGoogle Scholar
• Hodis E, Watson IR, Kryukov GV, et al. A landscape of driver mutations in melanoma. Cell 2012;150(2):251-63
   PubMed Web of Science ®Google Scholar
• Kovesdi D, Bell SE, Turner M. The development of mature B lymphocytes requires the combined function of CD19 and the p110delta subunit of PI3K. Self Nonself 2010;1(2):144-53
   PubMedGoogle Scholar
• Banham-Hall E, Clatworthy MR, Okkenhaug K. The therapeutic potential for PI3K inhibitors in autoimmune rheumatic diseases. Open Rheumatol J 2012;6:245-58
   PubMedGoogle Scholar
• Winkler DG, Faia KL, DiNitto JP, et al. PI3K-delta and PI3K-gamma inhibition by IPI-145 abrogates immune responses and suppresses activity in autoimmune and inflammatory disease models. Chem Biol 2013;20(11):1364-74
   PubMed Web of Science ®Google Scholar
• Ladygina N, Gottipati S, Ngo K, et al. PI3Kgamma kinase activity is required for optimal T-cell activation and differentiation. Eur J Immunol 2013;43(12):3183-96
   PubMedGoogle Scholar
• Chang JE, Kahl BS. PI3-kinase inhibitors in chronic lymphocytic leukemia. Curr Hematol Malig Rep 2014;9(1):33-43
   PubMedGoogle Scholar
• Ito K, Caramori G, Adcock IM. Therapeutic potential of phosphatidylinositol 3-kinase inhibitors in inflammatory respiratory disease. J Pharmacol Exp Ther 2007;321(1):1-8
   PubMed Web of Science ®Google Scholar
• Castor MG, Rezende BM, Bernardes PT, et al. PI3Kgamma controls leukocyte recruitment, tissue injury, and lethality in a model of graft-versus-host disease in mice. J Leukoc Biol 2011;89(6):955-64
   PubMedGoogle Scholar
• So L, Yea SS, Oak JS, et al. Selective inhibition of phosphoinositide 3-kinase p110alpha preserves lymphocyte function. J Biol Chem 2013;288(8):5718-31
   PubMed Web of Science ®Google Scholar
• Phase 1b Trial of BGJ398/BYL719 in solid tumors. Available from: http://clinicaltrials.gov/show/NCT01928459
   Google Scholar
• Dose escalation study of MLN1117 in subjects with advanced cancer. Available from: http://clinicaltrials.gov/ct2/show/NCT01449370
   Google Scholar
• A phase I/IIa, first time in human, study of GSK2636771 in subjects with advanced solid tumors with phosphatase and tensin homolog (PTEN) deficiency. Available from: http://clinicaltrials.gov/show/NCT01458067
   Google Scholar
• A phase I/IB trial for the evaluation of sar260301 in monotherapy or in combination with vemurafenib in patients with various advanced cancer. Available from: http://clinicaltrials.gov/ct2/show/NCT01673737
   Google Scholar
• Wu X, Ragupathi G, Panageas K, et al. Accelerated tumor growth mediated by sublytic levels of antibody-induced complement activation is associated with activation of the PI3K/AKT survival pathway. Clin Cancer Res 2013;19(17):4728-39
   PubMedGoogle Scholar
• Saunders RN, Metcalfe MS, Nicholson ML. Rapamycin in transplantation: a review of the evidence. Kidney Int 2001;59(1):3-16
   PubMed Web of Science ®Google Scholar
• Wai LE, Fujiki M, Takeda S, et al. Rapamycin, but not cyclosporine or FK506, alters natural killer cell function. Transplantation 2008;85(1):145-9
   PubMedGoogle Scholar
• Hackstein H, Taner T, Zahorchak AF, et al. Rapamycin inhibits IL-4--induced dendritic cell maturation in vitro and dendritic cell mobilization and function in vivo. Blood 2003;101(11):4457-63
   PubMed Web of Science ®Google Scholar
• Fox R, Nhan TQ, Law GL, et al. PSGL-1 and mTOR regulate translation of ROCK-1 and physiological functions of macrophages. EMBO J 2007;26(2):505-15
   PubMedGoogle Scholar
• Weinstein SL, Finn AJ, Dave SH, et al. Phosphatidylinositol 3-kinase and mTOR mediate lipopolysaccharide-stimulated nitric oxide production in macrophages via interferon-beta. J Leukoc Biol 2000;67(3):405-14
   PubMedGoogle Scholar
• Boks MA, Kager-Groenland JR, Haasjes MS, et al. IL-10-generated tolerogenic dendritic cells are optimal for functional regulatory T cell induction – a comparative study of human clinical-applicable DC. Clin Immunol 2012;142(3):332-42
   PubMed Web of Science ®Google Scholar
• Baker AK, Wang R, Mackman N, Luyendyk JP. Rapamycin enhances LPS induction of tissue factor and tumor necrosis factor-alpha expression in macrophages by reducing IL-10 expression. Mol Immunol 2009;46(11-12):2249-55
   PubMedGoogle Scholar
• Weichhart T, Costantino G, Poglitsch M, et al. The TSC-mTOR signaling pathway regulates the innate inflammatory response. Immunity 2008;29(4):565-77
   PubMed Web of Science ®Google Scholar
• Araki K, Turner AP, Shaffer VO, et al. mTOR regulates memory CD8 T-cell differentiation. Nature 2009;460(7251):108-12
   PubMed Web of Science ®Google Scholar
• Jagannath C, Lindsey DR, Dhandayuthapani S, et al. Autophagy enhances the efficacy of BCG vaccine by increasing peptide presentation in mouse dendritic cells. Nat Med 2009;15(3):267-76
   PubMed Web of Science ®Google Scholar
• Wang Y, Wang XY, Subjeck JR, et al. Temsirolimus, an mTOR inhibitor, enhances anti-tumour effects of heat shock protein cancer vaccines. Br J Cancer 2011;104(4):643-52
   PubMed Web of Science ®Google Scholar
• Jiang Q, Weiss JM, Back T, et al. mTOR kinase inhibitor AZD8055 enhances the immunotherapeutic activity of an agonist CD40 antibody in cancer treatment. Cancer Res 2011;71(12):4074-84
   PubMed Web of Science ®Google Scholar
• Noh KH, Kang TH, Kim JH, et al. Activation of Akt as a mechanism for tumor immune evasion. Mol Ther 2009;17(3):439-47
   PubMedGoogle Scholar
• Wang Q, Li SH, Wang H, et al. Concomitant targeting of tumor cells and induction of T-cell response synergizes to effectively inhibit trastuzumab-resistant breast cancer. Cancer Res 2012;72(17):4417-28
   PubMed Web of Science ®Google Scholar
• A study of triciribine phosphate monohydrate (TCN-PM). Available from: http://clinicaltrials.gov/show/NCT01697293
   Google Scholar
• Triciribine and carboplatin in ovarian cancer. Available from: http://clinicaltrials.gov/ct2/show/NCT01690468
   Google Scholar
• Bonet C, Giuliano S, Ohanna M, et al. Aurora B is regulated by the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathway and is a valuable potential target in melanoma cells. J Biol Chem 2012;287(35):29887-98
   PubMedGoogle Scholar
• Goos JA, Coupe VM, Diosdado B, et al. Aurora kinase A (AURKA) expression in colorectal cancer liver metastasis is associated with poor prognosis. Br J Cancer 2013;109(9):2445-52
   PubMed Web of Science ®Google Scholar
• Traynor AM, Hewitt M, Liu G, et al. Phase I dose escalation study of MK-0457, a novel Aurora kinase inhibitor, in adult patients with advanced solid tumors. Cancer Chemother Pharmacol 2011;67(2):305-14
   PubMed Web of Science ®Google Scholar
• Shimomura T, Hasako S, Nakatsuru Y, et al. MK-5108, a highly selective Aurora-A kinase inhibitor, shows antitumor activity alone and in combination with docetaxel. Mol Cancer Ther 2010;9(1):157-66
   PubMedGoogle Scholar
• Manfredi MG, Ecsedy JA, Meetze KA, et al. Antitumor activity of MLN8054, an orally active small-molecule inhibitor of Aurora A kinase. Proc Natl Acad Sci U S A 2007;104(10):4106-11
   PubMedGoogle Scholar
• AZD1152 in patients with advanced solid malignancies. Available from: http://clinicaltrials.gov/ct2/show/NCT00338182
   Google Scholar
• Gabler K, Rolvering C, Kaczor J, et al. Cooperative effects of Janus and Aurora kinase inhibition by CEP701 in cells expressing Jak2V617F. J Cell Mol Med 2013;17(2):265-76
   PubMedGoogle Scholar
• Glant TT, Besenyei T, Kadar A, et al. Differentially expressed epigenome modifiers, including aurora kinases A and B, in immune cells in rheumatoid arthritis in humans and mouse models. Arthritis Rheum 2013;65(7):1725-35
   PubMedGoogle Scholar
• Wu X, Li J, Zhu M, et al. Protein kinase C inhibitor AEB071 targets ocular melanoma harboring GNAQ mutations via effects on the PKC/Erk1/2 and PKC/NF-kappaB pathways. Mol Cancer Ther 2012;11(9):1905-14
   PubMedGoogle Scholar
• Chen X, Wu Q, Tan L, et al. Combined PKC and MEK inhibition in uveal melanoma with GNAQ and GNA11 mutations. Oncogene 2013. [Epub ahead of print]
   Google Scholar
• Sagoo MS, Harbour JW, Stebbing J, Bowcock AM. Combined PKC and MEK inhibition for treating metastatic uveal melanoma. Oncogene 2014. [Epub ahead of print]
   PubMedGoogle Scholar
• Wu X, Zhu M, Fletcher JA, et al. The protein kinase C inhibitor enzastaurin exhibits antitumor activity against uveal melanoma. PLoS One 2012;7(1):e29622
   Google Scholar
• Cerne JZ, Hartig SM, Hamilton MP, et al. Protein kinase C inhibitors sensitize GNAQ mutant uveal melanoma cells to ionizing radiation. Invest Ophthalmol Vis Sci 2014;55(4):2130-9
   PubMedGoogle Scholar
• Safety and efficacy of AEB071 in metastatic uveal melanoma patients. Available from: http://clinicaltrials.gov/ct2/show/NCT01430416
   Google Scholar
• Wagner J, von Matt P, Sedrani R, et al. Discovery of 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)quinazolin-4-yl]pyrrole-2,5-dione (AEB071), a potent and selective inhibitor of protein kinase C isotypes. J Med Chem 2009;52(20):6193-6
   PubMed Web of Science ®Google Scholar
• Skvara H, Dawid M, Kleyn E, et al. The PKC inhibitor AEB071 may be a therapeutic option for psoriasis. J Clin Invest 2008;118(9):3151-9
   PubMed Web of Science ®Google Scholar
• He X, Koenen HJ, Smeets RL, et al. Targeting PKC in Human T Cells Using Sotrastaurin (AEB071) Preserves Regulatory T Cells and Prevents IL-17 Production. J Invest Dermatol 2014;134(4):975-83
   PubMed Web of Science ®Google Scholar
• Lee MR, Duan W, Tan SL. Protein kinase C isozymes as potential therapeutic targets in immune disorders. Expert Opin Ther Targets 2008;12(5):535-52
   PubMed Web of Science ®Google Scholar
• Verdelli D, Nobili L, Todoerti K, et al. Molecular targeting of the PKC-beta inhibitor enzastaurin (LY317615) in multiple myeloma involves a coordinated downregulation of MYC and IRF4 expression. Hematol Oncol 2009;27(1):23-30
   PubMedGoogle Scholar
• Farren MR, Carlson LM, Lee KP. Tumor-mediated inhibition of dendritic cell differentiation is mediated by down regulation of protein kinase C beta II expression. Immunol Res 2010;46(1-3):165-76
   PubMed Web of Science ®Google Scholar
• Kong KF, Altman A. In and out of the bull’s eye: protein kinase Cs in the immunological synapse. Trends Immunol 2013;34(5):234-42
   PubMedGoogle Scholar
• Sun Z, Arendt CW, Ellmeier W, et al. PKC-theta is required for TCR-induced NF-kappaB activation in mature but not immature T lymphocytes. Nature 2000;404(6776):402-7
   PubMedGoogle Scholar
• Anderson K, Fitzgerald M, Dupont M, et al. Mice deficient in PKC theta demonstrate impaired in vivo T cell activation and protection from T cell-mediated inflammatory diseases. Autoimmunity 2006;39(6):469-78
   PubMed Web of Science ®Google Scholar
• Healy AM, Izmailova E, Fitzgerald M, et al. PKC-theta-deficient mice are protected from Th1-dependent antigen-induced arthritis. J Immunol 2006;177(3):1886-93
   PubMed Web of Science ®Google Scholar
• Weckbecker G, Pally C, Beerli C, et al. Effects of the novel protein kinase C inhibitor AEB071 (Sotrastaurin) on rat cardiac allograft survival using single agent treatment or combination therapy with cyclosporine, everolimus or FTY720. Transpl Int 2010;23(5):543-52
   PubMed Web of Science ®Google Scholar
• Bigaud M, Wieczorek G, Beerli C, et al. Sotrastaurin (AEB071) alone and in combination with cyclosporine A prolongs survival times of non-human primate recipients of life-supporting kidney allografts. Transplantation 2012;93(2):156-64
   PubMed Web of Science ®Google Scholar
• Sommerer C, Zeier M. AEB071 – a promising immunosuppressive agent. Clin Transplant 2009;23(Suppl 21):15-18
   PubMedGoogle Scholar
• Schonherr M, Bhattacharya A, Kottek T, et al. Genomewide RNAi screen identifies protein kinase Cbeta and new members of mitogen-activated protein kinase pathway as regulators of melanoma cell growth and metastasis. Pigment Cell Melanoma Res 2014;27(3):418-30
   PubMedGoogle Scholar
• Romano S, Nappo G, Cali G, et al. Synergy between enzastaurin doxorubicin in inducing melanoma apoptosis. Pigment Cell Melanoma Res 2013;26(6):900-11
   PubMedGoogle Scholar
• Hanauske AR, Oberschmidt O, Hanauske-Abel H, et al. Antitumor activity of enzastaurin (LY317615.HCl) against human cancer cell lines and freshly explanted tumors investigated in in-vitro [corrected] soft-agar cloning experiments. Invest New Drugs 2007;25(3):205-10
   PubMed Web of Science ®Google Scholar
• Matsuoka H, Tsubaki M, Yamazoe Y, et al. Tamoxifen inhibits tumor cell invasion and metastasis in mouse melanoma through suppression of PKC/MEK/ERK and PKC/PI3K/Akt pathways. Exp Cell Res 2009;315(12):2022-32
   PubMedGoogle Scholar
• Scortegagna M, Ruller C, Feng Y, et al. Genetic inactivation or pharmacological inhibition of Pdk1 delays development and inhibits metastasis of Braf::pten melanoma. Oncogene 2013. [Epub ahead of print]
   PubMedGoogle Scholar
• Tozer RG, Burdette-Radoux S, Berlanger K, et al. A randomized phase II study of two schedules of bryostatin-1 (NSC339555) in patients with advanced malignant melanoma: a National Cancer Institute of Canada Clinical Trials Group study. Invest New Drugs 2002;20(4):407-12
   PubMed Web of Science ®Google Scholar
• Propper DJ, Macaulay V, O’Byrne KJ, et al. A phase II study of bryostatin 1 in metastatic malignant melanoma. Br J Cancer 1998;78(10):1337-41
   PubMedGoogle Scholar
• Zhao D, Amria S, Hossain A, et al. Enhancement of HLA class II-restricted CD4+ T cell recognition of human melanoma cells following treatment with bryostatin-1. Cell Immunol 2011;271(2):392-400
   PubMed Web of Science ®Google Scholar
• Yan W, Chen WC, Liu Z, Huang L. Bryostatin-I: a dendritic cell stimulator for chemokines induction and a promising adjuvant for a peptide based cancer vaccine. Cytokine 2010;52(3):238-44
   PubMed Web of Science ®Google Scholar
• Parviz M, Chin CS, Graham LJ, et al. Successful adoptive immunotherapy with vaccine-sensitized T cells, despite no effect with vaccination alone in a weakly immunogenic tumor model. Cancer Immunol Immunother 2003;52(12):739-50
   PubMedGoogle Scholar
• Kmieciak M, Basu D, Payne KK, et al. Activated NKT cells and NK cells render T cells resistant to myeloid-derived suppressor cells and result in an effective adoptive cellular therapy against breast cancer in the FVBN202 transgenic mouse. J Immunol 2011;187(2):708-17
   PubMed Web of Science ®Google Scholar
• Payne KK, Zoon CK, Wan W, et al. Peripheral blood mononuclear cells of patients with breast cancer can be reprogrammed to enhance anti-HER-2/neu reactivity and overcome myeloid-derived suppressor cells. Breast Cancer Res Treat 2013;142(1):45-57
   PubMed Web of Science ®Google Scholar