Targeting the RAS oncogene

Bibliography

• Fernandez-Medarde A, Santos E. Ras in cancer and developmental diseases. Genes Cancer 2011;2(3):344-58
   PubMedGoogle Scholar
• Prior IA, Lewis PD, Mattos C. A comprehensive survey of ras mutations in cancer. Cancer Res 2012;72(10):2457-6
   PubMed Web of Science ®Google Scholar
• Malumbres M, Barbacid M. RAS oncogenes: the first 30 years. Nat Rev Cancer 2003;3(6):459-65
   PubMed Web of Science ®Google Scholar
• Karreth FA, Tuveson DA. Modelling oncogenic ras/raf signalling in the mouse. Curr Opin Genet Dev 2009;19(1):4-11
   PubMed Web of Science ®Google Scholar
• Rajalingam K, Schreck R, Rapp UR, Albert S. Ras oncogenes and their downstream targets. Biochim Biophys Acta 2007;1773(8):1177-95
   PubMed Web of Science ®Google Scholar
• Dhillon AS, Hagan S, Rath O, Kolch W. MAP kinase signalling pathways in cancer. Oncogene 2007;26(22):3279-90
   PubMed Web of Science ®Google Scholar
• Franke TF. PI3K/akt: getting it right matters. Oncogene 2008;27(50):6473-88
   PubMed Web of Science ®Google Scholar
• Gysin S, Salt M, Young A, McCormick F. Therapeutic strategies for targeting ras proteins. Genes Cancer 2011;2(3):359-72
   PubMedGoogle Scholar
• Appels NM, Beijnen JH, Schellens JH. Development of farnesyl transferase inhibitors: a review. Oncologist 2005;10(8):565-78
   PubMed Web of Science ®Google Scholar
• Whyte DB, Kirschmeier P, Hockenberry TN, K- and N-ras are geranylgeranylated in cells treated with farnesyl protein transferase inhibitors. J Biol Chem 1997;272(22):14459-64
   PubMed Web of Science ®Google Scholar
• Rotblat B, Ehrlich M, Haklai R, Kloog Y. The ras inhibitor farnesylthiosalicylic acid (salirasib) disrupts the spatiotemporal localization of active ras: a potential treatment for cancer. Methods Enzymol 2008;439:467-89
   PubMed Web of Science ®Google Scholar
• Vigil D, Cherfils J, Rossman KL, Der CJ. Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy? Nat Rev Cancer 2010;10(12):842-57
   PubMed Web of Science ®Google Scholar
• Downward J. Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer 2003;3(1):11-22
   PubMed Web of Science ®Google Scholar
• Yeh TC, Marsh V, Bernat BA, Biological characterization of ARRY-142886 (AZD6244), a potent, highly selective mitogen-activated protein kinase kinase 1/2 inhibitor. Clin Cancer Res 2007;13(5):1576-83
   PubMed Web of Science ®Google Scholar
• Huang J, Manning BD. A complex interplay between akt, TSC2 and the two mTOR complexes. Biochem Soc Trans 2009;37(Pt 1):217-22
   PubMed Web of Science ®Google Scholar
• Weinstein IB. Cancer. addiction to oncogenes--the achilles heal of cancer. Science 2002;297(5578):63-4
   PubMed Web of Science ®Google Scholar
• Chen G, Oh S, Monia BP, Stacey DW. Antisense oligonucleotides demonstrate a dominant role of c-ki-RAS proteins in regulating the proliferation of diploid human fibroblasts. J Biol Chem 1996;271(45):28259-65
   PubMed Web of Science ®Google Scholar
• Cunningham CC, Holmlund JT, Geary RS, A phase I trial of H-ras antisense oligonucleotide ISIS 2503 administered as a continuous intravenous infusion in patients with advanced carcinoma. Cancer 2001;92(5):1265-71
   PubMed Web of Science ®Google Scholar
• Perez RP, Smith JW III, Alberts SR, Phase II trial of ISIS 2503, an antisense inhibitor of H-ras, in patients (pts) with advanced pancreatic carcinoma (CA). ASCO Meet Abstr 2001;20:628
   Google Scholar
• Saleh M, Posey J, Pleasant L, A phase II trial of ISIS 2503, an antisense inhibitor of H-ras, as first line therapy for advanced colorectal carcinoma. ASCO Meet Abstr 2000;19:1258
   Google Scholar
• Dang T, Johnson DH, Kelly K, Multicenter phase II trial of an antisense inhibitor of H-ras (ISIS-2503) in advanced non-small cell lung cancer (NSCLC). ASCO Meet Abstr 2001;20:1325
   Google Scholar
• Goldsmith G, Larocca RV, Glisson S, Phase 2 trial of ISIS 2503, an antisense inhibitor of h-ras, in combination with docetaxel for patients with previously treated advanced non-small cell lung cancer. ASCO Meet Abstr 2003;22:941
   Google Scholar
• Alberts SR, Schroeder M, Erlichman C, F,Jr, et al. Gemcitabine and ISIS-2503 for patients with locally advanced or metastatic pancreatic adenocarcinoma: a north central cancer treatment group phase II trial. J Clin Oncol 2004;22(24):4944-50
   PubMed Web of Science ®Google Scholar
• Saleh MN, Irwin D, Burton G, Phase 2 trial of ISIS 2503, an antisense inhibitor of h-ras, in combination with weekly paclitaxel in the treatment of patients with metastatic breast cancer. ASCO Meet Abstr 2003;22:829
   Google Scholar
• Lledo S, Alfonso R, Alino SF. Antisense gene therapy using anti-k-ras and antitelomerase oligonucleotides in colorectal cancer. Rev Esp Enferm Dig 2005;97(7):472-80
   PubMed Web of Science ®Google Scholar
• Andreyev HJ, Ross PJ, Cunningham D, Clarke PA. Antisense treatment directed against mutated ki-ras in human colorectal adenocarcinoma. Gut 2001;48(2):230-7
   PubMed Web of Science ®Google Scholar
• Brummelkamp TR, Bernards R, Agami R. Stable suppression of tumorigenicity by virus-mediated RNA interference. Cancer Cell 2002;2(3):243-7
   PubMed Web of Science ®Google Scholar
• Fleming JB, Shen GL, Holloway SE, Molecular consequences of silencing mutant K-ras in pancreatic cancer cells: justification for K-ras-directed therapy. Mol Cancer Res 2005;3(7):413-12
   PubMed Web of Science ®Google Scholar
• Smakman N, Veenendaal LM, van Diest P, Dual effect of kras(D12) knockdown on tumorigenesis: increased immune-mediated tumor clearance and abrogation of tumor malignancy. Oncogene 2005;24(56):8338-42
   PubMed Web of Science ®Google Scholar
• Yang G, Thompson JA, Fang B, Liu J. Silencing of H-ras gene expression by retrovirus-mediated siRNA decreases transformation efficiency and tumorgrowth in a model of human ovarian cancer. Oncogene 2003;22(36):5694-701
   PubMed Web of Science ®Google Scholar
• Zhang Z, Jiang G, Yang F, Wang J. Knockdown of mutant K-ras expression by adenovirus-mediated siRNA inhibits the in vitro and in vivo growth of lung cancer cells. Cancer Biol Ther 2006;5(11):1481-6
   PubMed Web of Science ®Google Scholar
• Zhu H, Liang ZY, Ren XY, Liu TH. Small interfering RNAs targeting mutant K-ras inhibit human pancreatic carcinoma cells growth in vitro and in vivo. Cancer Biol Ther 2006;5(12):1693-8
   PubMed Web of Science ®Google Scholar
• End DW, Smets G, Todd AV, Characterization of the antitumor effects of the selective farnesyl protein transferase inhibitor R115777 in vivo and in vitro. Cancer Res 2001;61(1):131-7
   PubMed Web of Science ®Google Scholar
• Liu M, Bryant MS, Chen J, Antitumor activity of SCH 66336, an orally bioavailable tricyclic inhibitor of farnesyl protein transferase, in human tumor xenograft models and wap-ras transgenic mice. Cancer Res 1998;58(21):4947-56
   PubMed Web of Science ®Google Scholar
• Rose WC, Lee FY, Fairchild CR, Preclinical antitumor activity of BMS-214662, a highly apoptotic and novel farnesyltransferase inhibitor. Cancer Res 2001;61(20):7507-1
   PubMed Web of Science ®Google Scholar
• Adjei AA, Mauer A, Bruzek L, Phase II study of the farnesyl transferase inhibitor R115777 in patients with advanced non-small-cell lung cancer. J Clin Oncol 2003;21(9):1760-6
   PubMed Web of Science ®Google Scholar
• Cohen SJ, Ho L, Ranganathan S, Phase II and pharmacodynamic study of the farnesyltransferase inhibitor R115777 as initial therapy in patients with metastatic pancreatic adenocarcinoma. J Clin Oncol 2003;21(7):1301-6
   PubMed Web of Science ®Google Scholar
• Johnston SR, Hickish T, Ellis P, Phase II study of the efficacy and tolerability of two dosing regimens of the farnesyl transferase inhibitor, R115777, in advanced breast cancer. J Clin Oncol 2003;21(13):2492-9
   PubMed Web of Science ®Google Scholar
• Sparano JA, Moulder S, Kazi A, Phase II trial of tipifarnib plus neoadjuvant doxorubicin-cyclophosphamide in patients with clinical stage IIB-IIIC breast cancer. Clin Cancer Res 2009;15(8):2942-8
   PubMed Web of Science ®Google Scholar
• Fenaux P, Raza A, Mufti GJ, A multicenter phase 2 study of the farnesyltransferase inhibitor tipifarnib in intermediate- to high-risk myelodysplastic syndrome. Blood 2007;109(10):4158-63
   PubMed Web of Science ®Google Scholar
• Jabbour E, Kantarjian H, Ravandi F, A phase 1-2 study of a farnesyltransferase inhibitor, tipifarnib, combined with idarubicin and cytarabine for patients with newly diagnosed acute myeloid leukemia and high-risk myelodysplastic syndrome. Cancer 2011;117(6):1236-44
   PubMed Web of Science ®Google Scholar
• Harousseau JL, Martinelli G, Jedrzejczak WW, A randomized phase 3 study of tipifarnib compared with best supportive care, including hydroxyurea, in the treatment of newly diagnosed acute myeloid leukemia in patients 70 years or older. Blood 2009;114(6):1166-73
   PubMed Web of Science ®Google Scholar
• Rao S, Cunningham D, de Gramont A, Phase III double-blind placebo-controlled study of farnesyl transferase inhibitor R115777 in patients with refractory advanced colorectal cancer. J Clin Oncol 2004;22(19):3950-7
   PubMed Web of Science ®Google Scholar
• Van Cutsem E, van de Velde H, Karasek P, Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J Clin Oncol 2004;22(8):1430-8
   PubMed Web of Science ®Google Scholar
• Blumenschein G, Ludwig C, Thomas G, A randomized phase III trial comparing lonafarnib/carboplatin/paclitaxel versus carboplatin/paclitaxel (CP) in chemotherapy-naive patients with advanced or metastatic non-small cell lung cancer (NSCLC). Lung Cancer 2005;49(Suppl 2):S30
   Web of Science ®Google Scholar
• Sepp-Lorenzino L, Ma Z, Rands E, A peptidomimetic inhibitor of farnesyl:protein transferase blocks the anchorage-dependent and -independent growth of human tumor cell lines. Cancer Res 1995;55(22):5302-9
   PubMed Web of Science ®Google Scholar
• Sun J, Qian Y, Hamilton AD, Sebti SM. Both farnesyltransferase and geranylgeranyltransferase I inhibitors are required for inhibition of oncogenic K-ras prenylation but each alone is sufficient to suppress human tumor growth in nude mouse xenografts. Oncogene 1998;16(11):1467-73
   PubMed Web of Science ®Google Scholar
• Charette N, De Saeger C, Lannoy V, Salirasib inhibits the growth of hepatocarcinoma cell lines in vitro and tumor growth in vivo through ras and mTOR inhibition. Mol Cancer 2010;9:256
   PubMed Web of Science ®Google Scholar
• Goldberg L, Ocherashvilli A, Daniels D, Salirasib (farnesyl thiosalicylic acid) for brain tumor treatment: a convection-enhanced drug delivery study in rats. Mol Cancer Ther 2008;7(11):3609-16
   PubMed Web of Science ®Google Scholar
• Haklai R, Elad-Sfadia G, Egozi Y, Kloog Y. Orally administered FTS (salirasib) inhibits human pancreatic tumor growth in nude mice. Cancer Chemother Pharmacol 2008;61(1):89-96
   PubMed Web of Science ®Google Scholar
• Zundelevich A, Elad-Sfadia G, Haklai R, Kloog Y. Suppression of lung cancer tumor growth in a nude mouse model by the ras inhibitor salirasib (farnesylthiosalicylic acid). Mol Cancer Ther 2007;6(6):1765-73
   PubMed Web of Science ®Google Scholar
• Laheru D, Shah P, Rajeshkumar NV, Integrated preclinical and clinical development of S-trans, trans-farnesylthiosalicylic acid (FTS, salirasib) in pancreatic cancer. Invest New Drugs 2012;30(6):2391-9
   PubMed Web of Science ®Google Scholar
• Tsimberidou AM, Rudek MA, Hong D, Phase 1 first-in-human clinical study of S-trans,trans-farnesylthiosalicylic acid (salirasib) in patients with solid tumors. Cancer Chemother Pharmacol 2010;65(2):235-41
   PubMed Web of Science ®Google Scholar
• Carnero A. The PKB/AKT pathway in cancer. Curr Pharm Des 2010;16(1):34-
   PubMed Web of Science ®Google Scholar
• Brugarolas J. Renal-cell carcinoma--molecular pathways and therapies. N Engl J Med 2007;356(2):185-7
   PubMed Web of Science ®Google Scholar
• Maira SM, Pecchi S, Huang A, Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-kinase inhibitor. Mol Cancer Ther 2012;11(2):317-28
   PubMed Web of Science ®Google Scholar
• Bendell JC, Rodon J, Burris HA, Phase I, dose-escalation study of BKM120, an oral pan-class I PI3K inhibitor, in patients with advanced solid tumors. J Clin Oncol 2012;30(3):282-90
   PubMed Web of Science ®Google Scholar
• Herman SE, Gordon AL, Wagner AJ, Phosphatidylinositol 3-kinase-delta inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals. Blood 2010;116(12):2078-
   PubMed Web of Science ®Google Scholar
• Lannutti BJ, Meadows SA, Herman SE, CAL-101, a p110delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood 2011;117(2):591-4
   PubMed Web of Science ®Google Scholar
• Ikeda H, Hideshima T, Fulciniti M, PI3K/p110{delta} is a novel therapeutic target in multiple myeloma. Blood 2010;116(9):1460-8
   PubMed Web of Science ®Google Scholar
• Meadows SA, Vega F, Kashishian A, PI3Kdelta inhibitor, GS-1101 (CAL-101), attenuates pathway signaling, induces apoptosis, and overcomes signals from the microenvironment in cellular models of hodgkin lymphoma. Blood 2012;119(8):1897-900
   PubMed Web of Science ®Google Scholar
• Meadows SA, Kashishian A, Johnson D, CAL-101 (GS-1101), a specific inhibitor of phosphatidylinositol-3-kinase-delta (PI3K{delta}), disrupts signals from the microenvironment, induces apoptosis, and enhances the antitumor activity of everolimus (RAD001), an inhibitor of mammalian target of rapamycin (mTOR), in mantle cell lymphoma (MCL). ASH Annual Meet Abstr 2011;118(21):3730
   Google Scholar
• Kahl B, Byrd JC, Flinn IW, Clinical safety and activity in a phase 1 study of CAL-101, an isoform-selective inhibitor of phosphatidylinositol 3-kinase P110{delta}, in patients with relapsed or refractory non-hodgkin lymphoma. ASH Annual Meet Abstr 2010;116(21):1777
   Google Scholar
• Furman RR, Byrd JC, Brown JR, CAL-101, an isoform-selective inhibitor of phosphatidylinositol 3-kinase P110{delta}, demonstrates clinical activity and pharmacodynamic effects in patients with relapsed or refractory chronic lymphocytic leukemia. ASH Annual Meet Abstr 2010;116(21):55
   Google Scholar
• Sharman J, de Vos S, Leonard JP, A phase 1 study of the selective phosphatidylinositol 3-kinase-delta (PI3K{delta}) inhibitor, CAL-101 (GS-1101), in combination with rituximab and/or bendamustine in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). ASH Annual Meet Abstr 2011;118(21):1787
   Google Scholar
• de Vos S, Schreeder MT, Flinn IW, A phase 1 study of the selective phosphatidylinositol 3-kinase-delta (PI3K{delta}) inhibitor, cal-101 (GS-1101), in combination with rituximab and/or bendamustine in patients with previously treated, indolent non-hodgkin lymphoma (iNHL). ASH Annual Meet Abstr 2011;118(21):2699
   Google Scholar
• Furman RR, Barrientos JC, Sharman JP, A phase I/II study of the selective phosphatidylinositol 3-kinase-delta (PI3K{delta}) inhibitor, GS-1101 (CAL-101), with ofatumumab in patients with previously treated chronic lymphocytic leukemia (CLL). ASCO Meet Abstr 2012;30(15_Suppl):6518
   Google Scholar
• Luk SK, Piekorz RP, Nurnberg B, Tony To SS. The catalytic phosphoinositol 3-kinase isoform p110delta is required for glioma cell migration and invasion. Eur J Cancer 2012;48(1):149-57
   PubMed Web of Science ®Google Scholar
• Kashishian A, Meadows S, Steiner B, Lannutti B. Abstract 3555: Anti-tumor activity of CAL-101, a potent selective inhibitor of the p110{delta} isoform of PI3K, in models of human glioblastoma. Cancer Res 2011;71(8 Suppl):3555
   Google Scholar
• Yap TA, Yan L, Patnaik A, 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
• Lu W, Defeo-Jones D, Davis L, Abstract #3714: in vitro and in vivo antitumor activities of MK-2206, a new allosteric akt inhibitor. AACR Meet Abstr 2009;2009(2_Annual_Meeting):3714
   Google Scholar
• Hirai H, Sootome H, Nakatsuru Y, MK-2206, an allosteric akt inhibitor, enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivo. Mol Cancer Ther 2010;9(7):1956-67
   PubMed Web of Science ®Google Scholar
• Han HS, Swanton C, Janjigian YY, A phase I study of the AKT inhibitor (MK-2206) with concurrent trastuzumab and lapatinib in patients with HER2-positive solid tumors. ASCO Meet Abstr 2011;29(15_Suppl):3028
   Google Scholar
• Spencer A, Yoon S, Harrison SJ, Novel AKT inhibitor GSK2110183 shows favorable safety, pharmacokinetics, and clinical activity in multiple myeloma. preliminary results from a phase I first-time-in-human study. ASH Annual Meet Abstr 2011;118(21):1856
   Google Scholar
• Blake JF, Xu R, Bencsik JR, Discovery and preclinical pharmacology of a selective ATP-competitive akt inhibitor (GDC-0068) for the treatment of human tumors. J Med Chem 2012;55(18):8110-27
   PubMed Web of Science ®Google Scholar
• Davies BR, Greenwood H, Dudley P, Preclinical pharmacology of AZD5363, an inhibitor of AKT: pharmacodynamics, antitumor activity, and correlation of monotherapy activity with genetic background. Mol Cancer Ther 2012;11(4):873-87
   PubMed Web of Science ®Google Scholar
• Wu X, Zhang J, Zhen R, Trastuzumab anti-tumor efficacy in patient-derived esophageal squamous cell carcinoma xenograft (PDECX) mouse models. J Transl Med 2012;10(1):180
   PubMedGoogle Scholar
• Houghton PJ. Everolimus. Clin Cancer Res 2010;16(5):1368-72
   PubMed Web of Science ®Google Scholar
• Rini BI. Temsirolimus, an inhibitor of mammalian target of rapamycin. Clin Cancer Res 2008;14(5):1286-90
   PubMed Web of Science ®Google Scholar
• Hudes G, Carducci M, Tomczak P, Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007;356(22):2271-8
   PubMed Web of Science ®Google Scholar
• Motzer RJ, Escudier B, Oudard S, Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 2008;372(9637):449-56
   PubMed Web of Science ®Google Scholar
• Keedy VL. Treating metastatic soft-tissue or bone sarcomas - potential role of ridaforolimus. Onco Targets Ther 2012;5:153-60
   PubMed Web of Science ®Google Scholar
• Ridaforolimus. Drugs R D 2010;10(3):165-78
   PubMedGoogle Scholar
• Merck receives complete response letter from U.S. food and drug administration for investigational medicine ridaforolimus [Internet].: Merck & Co., Inc. Available from: http://www.merck.com/newsroom/news-release-archive/research-and-development/2012_0605.html updated June 5, 2012 [cited 9/3/2012]
   Google Scholar
• Liu TJ, Koul D, LaFortune T, NVP-BEZ235, a novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor, elicits multifaceted antitumor activities in human gliomas. Mol Cancer Ther 2009;8(8):2204-10
   PubMed Web of Science ®Google Scholar
• Santiskulvong C, Konecny GE, Fekete M, Dual targeting of phosphoinositide 3-kinase and mammalian target of rapamycin using NVP-BEZ235 as a novel therapeutic approach in human ovarian carcinoma. Clin Cancer Res 2011;17(8):2373-84
   PubMed Web of Science ®Google Scholar
• Serra V, Markman B, Scaltriti M, NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res 2008;68(19):8022-30
   PubMed Web of Science ®Google Scholar
• Herrera VA, Zeindl-Eberhart E, Jung A, The dual PI3K/mTOR inhibitor BEZ235 is effective in lung cancer cell lines. Anticancer Res 2011;31(3):849-54
   PubMed Web of Science ®Google Scholar
• Burris H, Rodon J, Sharma S, First-in-human phase I study of the oral PI3K inhibitor BEZ235 in patients (pts) with advanced solid tumors. ASCO Meet Abstr 2010;28(15_Suppl):3005
   Google Scholar
• Arkenau H, Jones SF, Kurkjian C, The PI3K/mTOR inhibitor BEZ235 given twice daily for the treatment of patients (pts) with advanced solid tumors. ASCO Meet Abstr 2012;30(15_Suppl):3097
   Google Scholar
• Krop IE, Saura C, Rodon Ahnert J, A phase I/IB dose-escalation study of BEZ235 in combination with trastuzumab in patients with PI3-kinase or PTEN altered HER2+ metastatic breast cancer. ASCO Meet Abstr 2012;30(15_suppl):508
   Google Scholar
• Wallin JJ, Edgar KA, Guan J, GDC-0980 is a novel class I PI3K/mTOR kinase inhibitor with robust activity in cancer models driven by the PI3K pathway. Mol Cancer Ther 2011;10(12):2426-3
   PubMed Web of Science ®Google Scholar
• . Wagner AJ, Bendell JC, Dolly S, 0980, an oral PI3K/mTOR inhibitor, administered QD in patients with advanced solid tumors. ASCO Meet Abstr 2011;29(15_Suppl):3020
   Google Scholar
• Drosten M, Dhawahir A, Sum EY, Genetic analysis of ras signalling pathways in cell proliferation, migration and survival. EMBO J 2010;29(6):1091-104
   PubMed Web of Science ®Google Scholar
• Karreth FA, Frese KK, DeNicola GM, C-raf is required for the initiation of lung cancer by K-ras(G12D). Cancer Discov 2011;1(2):128-36
   PubMed Web of Science ®Google Scholar
• Wilhelm SM, Adnane L, Newell P, Preclinical overview of sorafenib, a multikinase inhibitor that targets both raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol Cancer Ther 2008;7(10):3129-40
   PubMed Web of Science ®Google Scholar
• Lamuraglia M, Escudier B, Chami L, To predict progression-free survival and overall survival in metastatic renal cancer treated with sorafenib: pilot study using dynamic contrast-enhanced doppler ultrasound. Eur J Cancer 2006;42(15):2472-9
   PubMed Web of Science ®Google Scholar
• Llovet JM, Ricci S, Mazzaferro V, Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359(4):378-90
   PubMed Web of Science ®Google Scholar
• Abou-Alfa GK, Schwartz L, Ricci S, Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol 2006;24(26):4293-300
   PubMed Web of Science ®Google Scholar
• Davies H, Bignell GR, Cox C, Mutations of the BRAF gene in human cancer. Nature 2002;417(6892):949-54
   PubMed Web of Science ®Google Scholar
• Tsai J, Lee JT, Wang W, Discovery of a selective inhibitor of oncogenic B-raf kinase with potent antimelanoma activity. Proc Natl Acad Sci USA 2008;105(8):3041-6
   PubMed Web of Science ®Google Scholar
• Flaherty KT, Puzanov I, Kim KB, Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 2010;363(9):809-1
   PubMed Web of Science ®Google Scholar
• Ribas A, Kim KB, Schuchter LM, BRIM-2: an open-label, multicenter phase II study of vemurafenib in previously treated patients with BRAF V600E mutation-positive metastatic melanoma. ASCO Meet Abstr 2011;29(15_Suppl):8509
   Google Scholar
• Chapman PB, Hauschild A, Robert C, 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, 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
• Nazarian R, Shi H, Wang Q, 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
• Villanueva J, Vultur A, Lee JT, Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K. Cancer Cell 2010;18(6):683-95
   PubMed Web of Science ®Google Scholar
• Montagut C, Sharma SV, Shioda T, Elevated CRAF as a potential mechanism of acquired resistance to BRAF inhibition in melanoma. Cancer Res 2008;68(12):4853-61
   PubMed Web of Science ®Google Scholar
• Johannessen CM, Boehm JS, Kim SY, COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 2010;468(7326):968-72
   PubMed Web of Science ®Google Scholar
• Poulikakos PI, Zhang C, Bollag G, RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 2010;464(7287):427-30
   PubMed Web of Science ®Google Scholar
• Hatzivassiliou G, Song K, Yen I, RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 2010;464(7287):431-5
   PubMed Web of Science ®Google Scholar
• Heidorn SJ, Milagre C, Whittaker S, Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell 2010;140(2):209-21
   PubMed Web of Science ®Google Scholar
• Su F, Viros A, Milagre C, 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
• Solit DB, Garraway LA, Pratilas CA, BRAF mutation predicts sensitivity to MEK inhibition. Nature 2006;439(7074):358-62
   PubMed Web of Science ®Google Scholar
• Gilmartin AG, Bleam MR, Groy A, GSK1120212 (JTP-74057) is an inhibitor of MEK activity and activation with favorable pharmacokinetic properties for sustained in vivo pathway inhibition. Clin Cancer Res 2011;17(5):989-1000
   PubMed Web of Science ®Google Scholar
• Falchook GS, Lewis KD, Infante JR, 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
• Infante JR, Fecher LA, Falchook GS, Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial. Lancet Oncol 2012;13(8):773-81
   PubMed Web of Science ®Google Scholar
• Flaherty KT, Robert C, Hersey P, Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 2012;367(2):107-14
   PubMed Web of Science ®Google Scholar
• Friday BB, Yu C, Dy GK, BRAF V600E disrupts AZD6244-induced abrogation of negative feedback pathways between extracellular signal-regulated kinase and raf proteins. Cancer Res 2008;68(15):6145-53
   PubMed Web of Science ®Google Scholar
• O'Neil BH, Goff LW, Kauh JS, Phase II study of the mitogen-activated protein kinase 1/2 inhibitor selumetinib in patients with advanced hepatocellular carcinoma. J Clin Oncol 2011;29(17):2350-6
   PubMed Web of Science ®Google Scholar
• Kirkwood JM, Bastholt L, Robert C, Phase II, open-label, randomized trial of the MEK1/2 inhibitor selumetinib as monotherapy versus temozolomide in patients with advanced melanoma. Clin Cancer Res 2012;18(2):555-67
   PubMed Web of Science ®Google Scholar
• Bodoky G, Timcheva C, Spigel DR, A phase II open-label randomized study to assess the efficacy and safety of selumetinib (AZD6244 [ARRY-142886]) versus capecitabine in patients with advanced or metastatic pancreatic cancer who have failed first-line gemcitabine therapy. Invest New Drugs 2012;30(3):1216-23
   PubMed Web of Science ®Google Scholar
• Balmanno K, Chell SD, Gillings AS, Intrinsic resistance to the MEK1/2 inhibitor AZD6244 (ARRY-142886) is associated with weak ERK1/2 signalling and/or strong PI3K signalling in colorectal cancer cell lines. Int J Cancer 2009;125(10):2332-41
   PubMed Web of Science ®Google Scholar
• Gopal YN, Deng W, Woodman SE, Basal and treatment-induced activation of AKT mediates resistance to cell death by AZD6244 (ARRY-142886) in braf-mutant human cutaneous melanoma cells. Cancer Res 2010;70(21):8736-47
   PubMed Web of Science ®Google Scholar
• Little AS, Balmanno K, Sale MJ, Amplification of the driving oncogene, KRAS or BRAF, underpins acquired resistance to MEK1/2 inhibitors in colorectal cancer cells. Sci Signal 2011;4(166):ra17
   PubMed Web of Science ®Google Scholar
• Sos ML, Fischer S, Ullrich R, Identifying genotype-dependent efficacy of single and combined PI3K- and MAPK-pathway inhibition in cancer. Proc Natl Acad Sci USA 2009;106(43):18351-6
   PubMed Web of Science ®Google Scholar
• Greger JG, Eastman SD, Zhang V, Combinations of BRAF, MEK, and PI3K/mTOR inhibitors overcome acquired resistance to the BRAF inhibitor GSK2118436 dabrafenib, mediated by NRAS or MEK mutations. Mol Cancer Ther 2012;11(4):909-20
   PubMed Web of Science ®Google Scholar
• Kaelin WG Jr. Synthetic lethality: a framework for the development of wiser cancer therapeutics. Genome Med 2009;1(10):99
   PubMedGoogle Scholar
• Dobzhansky T, Krimbas C, Krimbas MG. Genetics of natural populations. xxix. is the genetic load in drosophila pseudoobscura a mutational or a balanced load? Genetics 1960;45(6):741-53
   PubMed Web of Science ®Google Scholar
• Solimini NL, Luo J, Elledge SJ. Non-oncogene addiction and the stress phenotype of cancer cells. Cell 2007;130(6):986-8
   PubMed Web of Science ®Google Scholar
• Barbie DA, Tamayo P, Boehm JS, Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature 2009;462(7269):108-12
   PubMed Web of Science ®Google Scholar
• Scholl C, Frohling S, Dunn IF, Synthetic lethal interaction between oncogenic KRAS dependency and STK33 suppression in human cancer cells. Cell 2009;137(5):821-34
   PubMed Web of Science ®Google Scholar
• Babij C, Zhang Y, Kurzeja RJ, STK33 kinase activity is nonessential in KRAS-dependent cancer cells. Cancer Res 2011;71(17):5818-26
   PubMed Web of Science ®Google Scholar
• Luo J, Emanuele MJ, Li D, A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the ras oncogene. Cell 2009;137(5):835-48
   PubMed Web of Science ®Google Scholar
• Singh A, Greninger P, Rhodes D, A gene expression signature associated with "K-ras addiction" reveals regulators of EMT and tumor cell survival. Cancer Cell 2009;15(6):489-500
   PubMed Web of Science ®Google Scholar
• Sarthy AV, Morgan-Lappe SE, Zakula D, Survivin depletion preferentially reduces the survival of activated K-ras-transformed cells. Mol Cancer Ther 2007;6(1):269-76
   PubMed Web of Science ®Google Scholar
• Meylan E, Dooley AL, Feldser DM, Requirement for NF-kappaB signalling in a mouse model of lung adenocarcinoma. Nature 2009;462(7269):104-7
   PubMed Web of Science ®Google Scholar
• Basu A, Pal D. Two faces of protein kinase cdelta: the contrasting roles of PKCdelta in cell survival and cell death. ScientificWorldJournal 2010;10:2272-84
   PubMed Web of Science ®Google Scholar
• Leitges M, Mayr M, Braun U, Exacerbated vein graft arteriosclerosis in protein kinase cdelta-null mice. J Clin Invest 2001;108(10):1505-12
   PubMed Web of Science ®Google Scholar
• Xia S, Forman LW, Faller DV. Protein kinase C delta is required for survival of cells expressing activated p21RAS. J Biol Chem 2007;282(18):13199-210
   PubMed Web of Science ®Google Scholar
• Xia S, Chen Z, Forman LW, Faller DV. PKCdelta survival signaling in cells containing an activated p21Ras protein requires PDK1. Cell Signal 2009;21(4):502-8
   PubMed Web of Science ®Google Scholar
• Chen Z, Forman LW, Miller KA, Protein kinase cdelta inactivation inhibits cellular proliferation and decreases survival in human neuroendocrine tumors. Endocr Relat Cancer 2011;18(6):759-71
   PubMed Web of Science ®Google Scholar
• Takashima A, Faller DV. Inhibition of protein kinase C delta induces apoptosis through JNK-H2AX pathway in melanoma. AACR Annual Meeting; 2013; In press
   Google Scholar
• Besse B, Soria J, Gomez-Roca C, A phase ib study to evaluate the PI3-kinase inhibitor GDC-0941 with paclitaxel (P) and carboplatin (C), with and without bevacizumab (BEV), in patients with advanced non-small cell lung cancer (NSCLC). ASCO Meet Abstr 2011;29(15):3044
   Google Scholar
• LoRusso P, Shapiro G, Pandya SS, A first-in-human phase ib study to evaluate the MEK inhibitor GDC-0973, combined with the pan-PI3K inhibitor GDC-0941, in patients with advanced solid tumors. ASCO Meet Abstr 2012;30(15):2566
   Google Scholar
• Moreno Garcia V, Baird RD, Shah KJ, A phase I study evaluating GDC-0941, an oral phosphoinositide-3 kinase (PI3K) inhibitor, in patients with advanced solid tumors or multiple myeloma. ASCO Meet Abstr 2011;29(15):3021
   Google Scholar
• Jimeno A, Herbst RS, Falchook GS, Final results from a phase I, dose-escalation study of PX-866, an irreversible, pan-isoform inhibitor of PI3 kinase. ASCO Meet Abstr 2010;28(15_Suppl):3089
   Google Scholar
• Jimeno A, Senzer NN, Rudin CM, PX-866 and docetaxel in patients with advanced solid tumors. ASCO Meet Abstr 2012;30(15_suppl):3024
   Google Scholar
• Patnaik A, Appleman LJ, Mountz JM, A first-in-human phase I study of intravenous PI3K inhibitor BAY 80-6946 in patients with advanced solid tumors: results of dose-escalation phase. ASCO Meet Abstr 2011;29(15_Suppl):3035
   Google Scholar
• Moldovan C, Soria J, LoRusso P, A phase I safety and pharmacokinetic (PK) study of the PI3K inhibitor XL147 (SAR245408) in combination with erlotinib in patients (pts) with advanced solid tumors. ASCO Meet Abstr 2010;28(15_Suppl):3070
   Google Scholar
• Traynor AM, Kurzrock R, Bailey HH, A phase I safety and pharmacokinetic (PK) study of the PI3K inhibitor XL147 (SAR245408) in combination with paclitaxel (P) and carboplatin (C) in patients (pts) with advanced solid tumors. ASCO Meet Abstr 2010;28(15_Suppl):3078
   Google Scholar
• Juric D, Rodon J, Gonzalez-Angulo AM, Abstract CT-01: BYL719, a next generation PI3K alpha specific inhibitor: preliminary safety, PK, and efficacy results from the first-in-human study. Cancer Res 2012;72(8 Suppl):CT-01
   Google Scholar
• Yaguchi S, Fukui Y, Koshimizu I, Antitumor activity of ZSTK474, a new phosphatidylinositol 3-kinase inhibitor. J Natl Cancer Inst 2006;98(8):545-56
   PubMedGoogle Scholar
• Chan TCK, Lapierre J, Ashwell MA, Abstract A230: discovery and characterization of ARQ 092, an ATP-independent, potent and selective inhibitor of AKT kinases. Mol Cancer Ther 2011;10(Suppl 1):A230
   Google Scholar
• Burris HA, Siu LL, Infante JR, Safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of the oral AKT inhibitor GSK2141795 (GSK795) in a phase I first-in-human study. ASCO Meet Abstr 2011;29(15_Suppl):3003
   Google Scholar
• Shih KC, Bendell JC, Reinert A, Phase I trial of an oral TORC1/TORC2 inhibitor (CC-223) in advanced solid and hematologic cancers. ASCO Meet Abstr 2012;30(15_Suppl):3006
   Google Scholar
• Banerji U, Dean EJ, Gonzalez M, First-in-human phase I trial of the dual mTORC1 and mTORC2 inhibitor AZD2014 in solid tumors. ASCO Meet Abstr 2012;30(15_Suppl):3004
   Google Scholar
• Bhagwat SV, Gokhale PC, Crew AP, Preclinical characterization of OSI-027, a potent and selective inhibitor of mTORC1 and mTORC2: distinct from rapamycin. Mol Cancer Ther 2011;10(8):1394-406
   PubMed Web of Science ®Google Scholar
• Yuan J, Mehta PP, Yin MJ, PF-04691502, a potent and selective oral inhibitor of PI3K and mTOR kinases with antitumor activity. Mol Cancer Ther 2011;10(11):2189-
   PubMed Web of Science ®Google Scholar
• Mallon R, Feldberg LR, Lucas J, Antitumor efficacy of PKI-587, a highly potent dual PI3K/mTOR kinase inhibitor. Clin Cancer Res 2011;17(10):3193-20
   PubMed Web of Science ®Google Scholar
• Cohen RB, Janne PA, Engelman JA, A phase I safety and pharmacokinetic (PK) study of PI3K/TORC1/TORC2 inhibitor XL765 (SAR245409) in combination with erlotinib (E) in patients (pts) with advanced solid tumors. ASCO Meet Abstr 2010;28(15_Suppl):3015
   Google Scholar
• Nghiemphu PL, Omuro AM, Cloughesy T, A phase I safety and pharmacokinetic study of XL765 (SAR245409), a novel PI3K/TORC1/TORC2 inhibitor, in combination with temozolomide (TMZ) in patients (pts) with newly diagnosed malignant glioma. ASCO Meet Abstr 2010;28(15_Suppl):3085
   Google Scholar
• Munster PN, van der Noll R, Voest EE, Phase I first-in-human study of the PI3 kinase inhibitor GSK2126458 (GSK458) in patients with advanced solid tumors (study P3K112826). ASCO Meet Abstr 2011;29(15_Suppl):3018
   Google Scholar
• O'Farrell M, Ventura R, Tai A, Matthews DJ. Abstract 3737: the PI3K/mTOR inhibitor PWT33597 regresses 786-0 renal xenografts. Cancer Res 2012;72(8 Suppl):3737
   Google Scholar
• Mahadevan D, Chiorean EG, Harris WB, 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;
   PubMed Web of Science ®Google Scholar
• Grothey A, Sobrero AF, Siena S, Results of a phase III randomized, double-blind, placebo-controlled, multicenter trial (CORRECT) of regorafenib plus best supportive care (BSC) versus placebo plus BSC in patients (pts) with metastatic colorectal cancer (mCRC) who have progressed after standard therapies. ASCO Meet Abstr 2012;30(4_Suppl):LBA385
   Google Scholar
• Eisen T, Joensuu H, Nathan PD, Regorafenib for patients with previously untreated metastatic or unresectable renal-cell carcinoma: a single-group phase 2 trial. Lancet Oncol 2012;13(10):1055-62
   PubMed Web of Science ®Google Scholar
• Stuart DD, Li N, Poon DJ, Abstract 3790: preclinical profile of LGX818: A potent and selective RAF kinase inhibitor. Cancer Res 2012;72(8 Suppl):3790
   Google Scholar
• Sharfman WH, Hodi FS, Lawrence DP, Results from the first-in-human (FIH) phase I study of the oral RAF inhibitor RAF265 administered daily to patients with advanced cutaneous melanoma. ASCO Meet Abstr 2011;29(15_Suppl):8508
   Google Scholar
• Su Y, Vilgelm AE, Kelley MC, RAF265 inhibits the growth of advanced human melanoma tumors. Clin Cancer Res 2012;18(8):2184-98
   PubMed Web of Science ®Google Scholar
• Finn RS, Javle MM, Tan BR, A phase I study of MEK inhibitor MEK162 (ARRY-438162) in patients with biliary tract cancer. ASCO Meet Abstr 2012;30(4_Suppl):220
   Google Scholar
• Kim K, Kong SY, Fulciniti M, Blockade of the MEK/ERK signalling cascade by AS703026, a novel selective MEK1/2 inhibitor, induces pleiotropic anti-myeloma activity in vitro and in vivo. Br J Haematol 2010;149(4):537-49
   PubMed Web of Science ®Google Scholar
• Infante JR, Gandhi L, Shapiro G, Phase lb combination trial of a MEK inhibitor, pimasertib (MSC1936369B), and a PI3K/mTOR inhibitor, SAR245409, in patients with locally advanced or metastatic solid tumors. ASCO Meet Abstr 2012;30(15_Suppl):TPS3118
   Google Scholar
• Lim HY, Yen C, Tak W, 86-9766 in combination with sorafenib as first-line systemic treatment for patients with unresectable hepatocellular carcinoma (HCC). ASCO Meet Abstr 2012;30(15_Suppl):4103
   Google Scholar
• Van Laethem J, Heinemann V, Martens UM, A phase I/II study of the MEK inhibitor BAY 86-9766 (BAY) in combination with gemcitabine (GEM) in patients with nonresectable, locally advanced or metastatic pancreatic cancer (PC): phase I dose-escalation results. ASCO Meet Abstr 2012;30(15_Suppl):4050
   Google Scholar
• Mala C, Neville NG, Haindl E, A phase I, first-in-human single ascending dose study of the MEK inhibitor WX-554 given to healthy male subjects. ASCO Meet Abstr 2010;28(15_Suppl):e13666
   Google Scholar
• Leijen S, Middleton MR, Tresca P, Phase I (ph) safety, pharmacodynamic (PD), and pharmacokinetic (PK) trial of a pure MEK inhibitor (i), RO4987655, in patients with advanced/metastatic solid tumor. ASCO Meet Abstr 2011;29(15_Suppl):3017
   Google Scholar
• Dong Q, Dougan DR, Gong X, Discovery of TAK-733, a potent and selective MEK allosteric site inhibitor for the treatment of cancer. Bioorg Med Chem Lett 2011;21(5):1315-19
   PubMed Web of Science ®Google Scholar
• Kumar V, Schuck EL, Pelletier RD, Pharmacokinetic characterization of a natural product-inspired novel MEK1 inhibitor E6201 in preclinical species. Cancer Chemother Pharmacol 2012;69(1):229-37
   PubMed Web of Science ®Google Scholar