1,113
Views
33
CrossRef citations to date
0
Altmetric
Review

PI3K/AKT/mTOR pathway inhibitors: the ideal combination partners for breast cancer therapies?

References

  • LoRusso PM. Mammalian target of rapamycin as a rational therapeutic target for breast cancer treatment. Oncology 2013;84(1):43-56
  • Desantis C, Ma J, Bryan L, Jemal A. Breast cancer statistics, 2013. CA Cancer J Clin 2014;64(1):52-62
  • Roche H, Vahdat LT. Treatment of metastatic breast cancer: second line and beyond. Ann Oncol 2011;22(5):1000-10
  • Miller TW, Balko JM, Arteaga CL. Phosphatidylinositol 3-kinase and antiestrogen resistance in breast cancer. J Clin Oncol 2011;29(33):4452-61
  • Anderson WF, Rosenberg PS, Katki HA. Tracking and evaluating molecular tumor markers with cancer registry data: HER2 and breast cancer. J Natl Cancer Inst 2014;106(5), 10.1093/jnci/dju093
  • Miller TW, Rexer BN, Garrett JT, Arteaga CL. Mutations in the phosphatidylinositol 3-kinase pathway: role in tumor progression and therapeutic implications in breast cancer. Breast Cancer Res 2011;13(6):224
  • NCCN.org. NCCN clinical practice guidelines in oncology: breast cancer. Version 3 2013
  • Liu P, Cheng H, Roberts TM, Zhao JJ. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov 2009;8(8):627-44
  • Contreras A, Herrera S, Wang T, et al. PIK3CA mutations and/or low PTEN predict resistance to combined anti-HER2 therapy with lapatinib and trastuzumab and without chemotherapy in TBCRC006, a neoadjuvant trial of HER2-positive breast cancer patients. abstract PD1-2 San Antonio Breast Cancer Symposium; 2013
  • Loibl S, Denkert C, Schneeweis A, et al. PIK3CA mutation predicts resistance to anti-HER2/chemotherapy in primary HER2-positive/hormone-receptor-positive breast cancer – Prospective analysis of 737 participants of the GeparSixto and GeparQuinto studies. abstract S4-06 San Antonio Breast Cancer Symposium; 2013
  • Sanchez CG, Ma CX, Crowder RJ, et al. Preclinical modeling of combined phosphatidylinositol-3-kinase inhibition with endocrine therapy for estrogen receptor-positive breast cancer. Breast Cancer Res 2011;13(2):R21
  • Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 2012;366(6):520-9
  • Bachelot T, Bourgier C, Cropet C, et al. Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study. J Clin Oncol 2012;30(22):2718-24
  • Wolff AC, Lazar AA, Bondarenko I, et al. Randomized phase III placebo-controlled trial of letrozole plus oral temsirolimus as first-line endocrine therapy in postmenopausal women with locally advanced or metastatic breast cancer. J Clin Oncol 2013;31(2):195-202
  • Chappell WH, Steelman LS, Long JM, et al. Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR inhibitors: rationale and importance to inhibiting these pathways in human health. Oncotarget 2011;2(3):135-64
  • Markman B, Tao JJ, Scaltriti M. PI3K pathway inhibitors: better not left alone. Curr Pharm Des 2013;19(5):895-906
  • O’Reilly KE, Rojo F, She QB, et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 2006;66(3):1500-8
  • Di Cosimo S, Baselga J. Phosphoinositide 3-kinase mutations in breast cancer: a “good” activating mutation? Clin Cancer Res 2009;15(16):5017-19
  • Maira SM, Pecchi S, Huang A, et al. Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-kinase inhibitor. Mol Cancer Ther 2012;11(2):317-28
  • 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;32(4):670-81
  • Pistilli B, Urruticoechea A, Chan S, et al. Ph IB/II study of BKM120 plus trastuzumab (T) in patients with T-resistant HER2+ advanced breast cancer (BC). Annals Oncol 2012;23:abstract 3180
  • Nanni P, Nicoletti G, Palladini A, et al. Multiorgan metastasis of human HER-2+ breast cancer in Rag2-/-;Il2rg-/- mice and treatment with PI3K inhibitor. PLoS One 2012;7(6):e39626
  • Maira M, Schnell C, Lollini P, et al. Preclinical and preliminary clinical activity of NVP-BKM120, an oral pan-class I PI3K inhibitor, in the brain. ESMO meeting abstracts; 2012. Suppl 15; 1675 (abstract)
  • A trial of BKM120 (a PI3K Inhibitor) in patients with triple negative metastatic breast cancer. Available from: www.clinicaltrials.gov/ct2/results?term=NCT01629615&Search=Search
  • Phase III study of BKM120/Placebo with fulvestrant in postmenopausal patients with hormone receptor positive HER2-negative locally advanced or metastatic breast cancer refractory to aromatase inhibitor. Available from: www.clinicaltrials.gov/ct2/results?term=NCT01610284&Search=Search
  • A Phase III Study of BKM120 with fulvestrant in patients with HR+,HER2-, AI treated, locally advanced or metastatic breast cancer who progressed on or after mTORi. Available from: www.clinicaltrials.gov/ct2/results?term=NCT01633060&Search=Search
  • Safety and efficacy of BKM120 and Lapatinib in HER2+/PI3K-activated, trastuzumab-resistant advanced breast cancer. Available from: www.clinicaltrials.gov/ct2/results?term=NCT01589861&Search=Search
  • A study of the experimental drug BKM120 with paclitaxel in patients with HER2 negative, locally advanced or metastatic breast cancer, with or without PI3K activation. Available from: www.clinicaltrials.gov/ct2/results?term=NCT01572727&Search=Search
  • NeoPHOEBE: neoadjuvant Trastuzumab + BKM120 in combination with weekly paclitaxel in HER2-positive primary breast cancer. Available from: www.clinicaltrials.gov/ct2/results?term=NCT01816594&Search=Search
  • Fritsch C, Huang A, Chatenay-Rivauday C, et al. Characterization of the novel and specific PI3Kalpha inhibitor NVP-BYL719 and development of the patient stratification strategy for clinical trials. Mol Cancer Ther 2014;13(5):1117-29
  • Huang A, Fritsch C, Wilson C, et al. Single agent activity of PIK3CA inhibitor BYL719 in a broad cancer cell line panel. Cancer Res 2012;72(8 Suppl 1):abstract 3749
  • A Study of BYL719 in adult patients with advanced solid malignancies, whose tumors have an alteration of the PIK3CA Gene. Available from: www.clinicaltrials.gov/ct2/results?term=NCT01219699&Search=Search
  • Gonzalez-Angulo AM, Juric D, Argilés G, et al. Safety, pharmacokinetics, and preliminary activity of the a-specific PI3K inhibitor BYL719: Results from the first-in-human study. ASCO Annual Meeting; 2013; Poster 2531
  • Juric D, Gonzalez-Angulo A, Burris H, et al. Preliminary safety, pharmacokinetics and anti-tumor activity of BYL719, an alpha-specific PI3K inhibitor in combination with fulvestrant: results from a phase I study. abstract P2-16-14 Presented at 36th SABCS Annual Meeting 2013
  • Brady SW, Zhang J, Seok D, et al. Enhanced PI3K p110alpha signaling confers acquired lapatinib resistance which can be effectively reversed by a p110alpha-selective PI3K inhibitor. Mol Cancer Ther 2013;13(1):60-70
  • Young CD, Pfefferle AD, Owens P, et al. Conditional loss of ErbB3 delays mammary gland hyperplasia induced by mutant PIK3CA without affecting mammary tumor latency, gene expression, or signaling. Cancer Res 2013;73(13):4075-85
  • Jia S, Liu Z, Zhang S, et al. Essential roles of PI(3)K-p110beta in cell growth, metabolism and tumorigenesis. Nature 2008;454(7205):776-9
  • Juric D, Krop I, Ramanathan R, et al. GDC-0032, a beta isoform-sparing PI3K inhibitor: results of a first-in-human phase Ia dose escalation study. abstract LB-64 In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; Washington, DC, USA; 6-10 April 2013; AACR, Philadelphia, PA, USA: 2013
  • Juric D, Infante JR, Krop IE, et al. Evaluation of tolerability and anti-tumor activity of GDC-0032, a PI3K inhibitor with enhanced activity against PIK3CA mutant tumors, administered to patients with advanced solid tumors. abstract 822 ESMO; 2013
  • Juric D, Infante JR, Krop IE, et al. Evaluation of tolerability and anti-tumor activity of GDC-0032, a PI3K inhibitor with enhanced activity against PIK3CA mutant tumors, administered to patients with advanced solid tumors. abstract P017 Presented at the European Cancer Congress (ECCO-ESMO-ESTRO); Amsterdam, Netherlands; 2013
  • A dose-escalation study to assess the safety, tolerability, and pharmacokinetics of GDC-0032 in combination with docetaxel or with paclitaxel in patients with HER2-negative locally recurrent or metastatic breast cancer. Available from: www.clinicaltrials.gov/ct2/results?term=NCT01862081&Search=Search
  • von Hoff D, LoRusso P, Demetri G, et al. A phase I dose-escalation study to evaluate GDC-0941, a pan-PI3K inhibitor, administered QD or BID in patients with advanced or metastatic solid tumors. J Clin Oncol 2011;29:abstract 3052
  • GDC-0941 and cisplatin in treating patients with androgen receptor-negative triple negative metastatic breast cancer. Available from: www.clinicaltrials.gov/ct2/results?term=NCT01918306&Search=Search
  • A Study of Paclitaxel with GDC-0941 versus paclitaxel with placebo in patients with locally recurrent or metastatic breast cancer. Available from: www.clinicaltrials.gov/ct2/results?term=NCT01740336&Search=Search
  • A Study of PI3-kinase inhibitor GDC-0941 in combination with paclitaxel, with and without bevacizumab or trastuzumab, in patients with locally recurrent or metastatic breast cancer. Available from: www.clinicaltrials.gov/ct2/results?term=NCT00960960&Search=Search
  • 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
  • Edelman G, Bedell C, Shapiro G, et al. A phase I dose-escalation study of XL147 (SAR245408), a PI3K inhibitor administered orally to patients (pts) with advanced malignancies. J Clin Oncol 2010;25(15 Suppl):abstract 3004
  • Moldovan C, Soria J, LoRusso P, et al. 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. J Clin Oncol 2010;28:abstract 3070
  • 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(4):873-87
  • Investigating safety, tolerability and efficacy of AZD5363 when combined with paclitaxel in breast cancer patients. Available from: www.clinicaltrials.gov/ct2/results?term=NCT01625286&Search=Search
  • Fulvestrant +/- Akt inhibition in advanced aromatase inhibitor resistant breast cancer. Available from: www.clinicaltrials.gov/ct2/results?term=NCT01992952&Search=Search
  • 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(7):1760-72
  • A study evaluating the safety and tolerability of GDC-0068 in patients with refractory solid tumors. Available from: www.clinicaltrials.gov/ct2/results?term=NCT01090960&Search=Search
  • A study evaluating the safety, tolerability, and pharmacokinetics of GDC-0973 in combination with GDC-0068 when administered in patients with locally advanced or metastatic solid tumors. Available from: www.clinicaltrials.gov/ct2/results?term=NCT01562275&Search=Search
  • Safety and pharmacology of GDC-0068 in combination with docetaxel, fluoropyrimidine plus oxaliplatin, paclitaxel, or enzalutamide in patients with advanced solid tumors. Available from: www.clinicaltrials.gov/ct2/results?term=NCT01362374&Search=Search
  • Burris HA, Siu LL, Infante JR, et al. Safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of the oral AKT inhibitor GSK2141795 (GSK795) in a phase I first-in-human study. J Clin Oncol 2011;29(15s):abstract 3003
  • Yap TA, Yan L, Patnaik A, et al. Final results of a translational phase I study assessing a QOD schedule of the potent ALK inhibitor MK-2206 incorporating predictive, pharmacodynamic (PD), and functional imaging biomarkers. J Clin Oncol 2011;29(15 Suppl):abstract 3001
  • Sangai T, Akcakanat A, Chen H, et al. Biomarkers of response to Akt inhibitor MK-2206 in breast cancer. J Clin Oncol 2012;30(15 Suppl):abstract 1054
  • MK2206 in combination with anastrozole, fulvestrant, or anastrozole and fulvestrant in treating postmenopausal women with metastatic breast cancer. Available from: www.clinicaltrials.gov/ct2/results?term=NCT01344031&Search=Search
  • Akt Inhibitor MK2206 in treating patients with advanced breast cancer. Available from: www.clinicaltrials.gov/ct2/results?term=NCT01277757&Search=Search
  • MK2206 and Paclitaxel in treating patients with locally advanced or metastatic solid tumors or metastatic breast cancer. Available from: www.clinicaltrials.gov/ct2/results?term=NCT01263145&Search=Search
  • Hurvitz SA, Dalenc F, Campone M, et al. A phase 2 study of everolimus combined with trastuzumab and paclitaxel in patients with HER2-overexpressing advanced breast cancer that progressed during prior trastuzumab and taxane therapy. Breast Cancer Res Treat 2013;141(3):437-46
  • Morrow PK, Wulf GM, Ensor J, et al. Phase I/II study of trastuzumab in combination with everolimus (RAD001) in patients with HER2-overexpressing metastatic breast cancer who progressed on trastuzumab-based therapy. J Clin Oncol 2011;29(23):3126-32
  • Andre F, O’Regan R, Ozguroglu M, et al. Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol 2014;15(6):580-91
  • Everolimus in combination with trastuzumab and paclitaxel in the treatment of HER2 positive locally advanced or metastatic breast cancer. Available from: www.clinicaltrials.gov/ct2/results?term=NCT00876395&Search=Search
  • S1207 Hormone therapy with or without everolimus in treating patients with breast cancer. Available from: www.clinicaltrials.gov/ct2/results?term=NCT01674140&Search=Search
  • Shih KC, Bendell JC, Reinert A, et al. Phase I trial of an oral TORC1/TORC2 inhibitor (CC-223) in advanced solid and hemtaologic cancers. J Clin Oncol 2012;30(15 Suppl):abstract 3006
  • 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: www.clinicaltrials.gov/ct2/results?term=NCT01177397&Search=Search
  • Varga A, Mita MM, Wu JJ, et al. Phase I expansion trial of an oral TORC1/TORC2 inhibitor (CC-223) in advanced solid tumors. J Clin Oncol 2013;31(15 Suppl):abstract 2606
  • Garcia-Garcia C, Ibrahim YH, Serra V, et al. Dual mTORC1/2 and HER2 blockade results in antitumor activity in preclinical models of breast cancer resistant to anti-HER2 therapy. Clin Cancer Res 2012;18(9):2603-12
  • De P, Sun Y, Wu H, et al. Efficacy of INK128, an mTORC1/mTORC2 kinase inhibitor, in breast cancer models driven by HER2-PI3K-AKT-mTOR pathway. J Clin Oncol 2012;30(15 Suppl):abstract 626
  • Dose escalation study of MLN0128 in combination with paclitaxel, with/without trastuzumab, in subjects with advanced solid malignancies. Available from: www.clinicaltrials.gov/ct2/results?term=NCT01351350&Search=Search
  • Markman B, Serra V, Scaltriti M, et al. Pharmacodynamic (PD) endpoints and cellular proliferation effects of NVP-BEZ235, a dual PI3K/mTOR inhibitor, in breast cancer cells and xenografts with wild-type (WT) and activating PI3K mutations. J Clin Oncol 2008;26(15 Suppl):14508
  • Brachmann SM, Hofmann I, Schnell C, et al. Specific apoptosis induction by the dual PI3K/mTor inhibitor NVP-BEZ235 in HER2 amplified and PIK3CA mutant breast cancer cells. Proc Natl Acad Sci USA 2009;106(52):22299-304
  • Krop IE, Saura C, Rodon Ahnert J, et al. 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. J Clin Oncol 2012;30(15 Suppl):abstract 508
  • Eichhorn PJ, Gili M, Scaltriti M, et al. Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. Cancer Res 2008;68(22):9221-30
  • Burris H, Rodon J, Sharma S, et al. First-in-human phase I study of the oral PI3K inhibitor BEZ-235 in patients (pts) with advanced solid tumors. J Clin Oncol 2010;28(15 Suppl):abstract 3005
  • Phase Ib/II Trial of BEZ235 with paclitaxel in patients with HER2 negative, locally advanced or metastatic breast cancer. Available from: www.clinicaltrials.gov/ct2/results?term=NCT01495247&Search=Search
  • Wallin JJ, Edgar KA, Guan J, et al. 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):2426-36
  • Dolly S, Bendell JC, Kindler HL, et al. Evaluation of tolerability and anti-tumor activity of GDC-0980, an oral PI3K/MTOR inhibitor, administered to patients with advanced solid tumors or non-Hodgkin’s lymphoma. abstract 803 ESMO; 2013
  • Brana I, LoRusso P, Baselga J, et al. A phase I dose-escalation study of the safety, pharmacokinetics (PK), and pharmacodynamics of XL765 (SAR245409), a PI3K/TORC1/TORC2 inhibitor administered orally to patients (pts) with advanced malignancies. J Clin Oncol 2010;28(15 Suppl):3030
  • Study of XL147 (SAR245408) or XL765 (SAR245409) in combination with letrozole in subjects with breast cancer. Available from: www.clinicaltrials.gov/ct2/results?term=NCT01082068&Search=Search
  • Andre F, Campone M, O’Regan R, et al. Phase I study of everolimus plus weekly paclitaxel and trastuzumab in patients with metastatic breast cancer pretreated with trastuzumab. J Clin Oncol 2010;28(34):5110-15
  • BYL719 plus letrozole or exemestane for patients with hormone-receptor positive locally-advanced unresectable or metastatic breast cancer. Available from: www.clinicaltrials.gov/ct2/results?term=NCT01870505&Search=Search
  • BYL719 and Letrozole in post-menopausal patients with hormone receptor-positive metastatic breast cancer. Available from: www.clinicaltrials.gov/ct2/results?term=NCT01791478&Search=Search
  • Study of Letrozole with or without BYL719 or buparlisib, for the neoadjuvant treatment of postmenopausal women. Available from: www.clinicaltrials.gov/ct2/results?term=NCT01923168&Search=Search
  • Finn RS, Dering J, Conklin D, et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res 2009;11(5):R77
  • Finn RS, Crown JP, Lang I, et al. Final results of a randomized Phase II study of PD 0332991, a cyclin-dependent kinase (CDK) 4/6 inhibitor, in combination with letrozole vs letrozole alone for first-line treatment of ER+/HER2– advanced breast cancer (PALOMA-1; TRIO-18). abstract CT101 Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 5 - 9 April 2014; San Diego, CA, USA
  • A Study of Palbociclib (PD-0332991) + Letrozole vs. Letrozole for 1st line treatment of postmenopausal women with er+/her2- advanced breast cancer (PALOMA-2). Available from: www.clinicaltrials.gov/ct2/results?term=NCT01740427&Search=Search
  • Shapiro GI. Cyclin-dependent kinase pathways as targets for cancer treatment. J Clin Oncol 2006;24(11):1770-83
  • Rader J, Russell M, Hart LS, et al. Dual CDK4/CDK6 inhibition induces cell cycle arrest and senescence in neuroblastoma. Clin Cancer Res 2013;19(22):6173-82
  • Kim S, Loo A, Chopra R, et al. LEE011: An orally bioavailable, selective small molecule inhibitor of CDK4/6--Reactivating Rb in cancer. abstract B264 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2013
  • Study of LEE011, BYL719 and letrozole in advanced ER+ breast cancer. Available from: www.clinicaltrials.gov/ct2/results?term=NCT01872260&Search=Search
  • Phase Ib/II Trial of LEE011 with everolimus (RAD001) and exemestane in the treatment of ER+ Her2- advanced breast cancer. Available from: www.clinicaltrials.gov/ct2/results?term=NCT01857193&Search=Search
  • Zhang Y, Moerkens M, Ramaiahgari S, et al. Elevated insulin-like growth factor 1 receptor signaling induces antiestrogen resistance through the MAPK/ERK and PI3K/Akt signaling routes. Breast Cancer Res 2011;13(3):R52
  • Kaufman PA, Ferrero JM, Bourgeois H, et al. A randomized, double-blind, placebo-controlled, Phase 2 study of AMG 479 with exemestane (E) or fulvestrant (F) in postmenopausal women with hormone-receptor positive (HR+) metastatic (M) or locally advanced (LA) breast cancer (BC). Cancer Res 2010;70(24 Suppl 2):abstract S1-4
  • Jalal SI, Strother RM, Sandusky G, et al. Phase I study of everolimus (E, RAD001) and ganitumab (G, AMG 479) in patients (pts) with advanced solid tumors. J Clin Oncol 2013;31(15 Suppl):abstract 2529
  • A Phase Ib/II study of the combination of BYL719 Plus AMG 479 in adult patients with selected solid tumors. Available from: www.clinicaltrials.gov/ct2/results?term=NCT01708161&Search=Search
  • A Trial of Oral BEZ235 and BKM120 in combination with paclitaxel with or without trastuzumab. Available from: www.clinicaltrials.gov/ct2/results?term=NCT01285466&Search=Search
  • Zambrano CC, Schuler MH, Machiels JH, et al. Phase lb study of buparlisib (BKM120) plus either paclitaxel (PTX) in advanced solid tumors (aST) or PTX plus trastuzumab (TZ) in HER2+ breast cancer (BC). J Clin Oncol 2014;32(5 Suppl):abstract 627
  • Ahnert JR, Schuler MH, Machiels JH, et al. Phase lb study of BEZ235 plus either paclitaxel (PTX) in advanced solid tumors (aST) or PTX plus trastuzumab (TZ) in HER2+ breast cancer (BC). J Clin Oncol 2014;32(5 Suppl):abstract 621
  • Han HS, Swanton C, Janjigian YY, et al. A phase I study of the AKT inhibitor (MK-2206) with concurrent trastuzumab and lapatinib in patients with HER2-positive solid tumors. J Clin Oncol 2011;29(15 Suppl):abstract 3028
  • Akt Inhibitor MK2206 in combination with lapatinib ditosylate in patients with advanced or metastatic solid tumors or breast cancer. Available from: www.clinicaltrials.gov/ct2/results?term=NCT01245205&Search=Search
  • Lapatinib Ditosylate and Akt Inhibitor MK2206 in treating women with metastatic breast cancer. Available from: www.clinicaltrials.gov/ct2/results?term=NCT01281163&Search=Search
  • Gayle SS, Arnold SL, O’Regan RM, Nahta R. Pharmacologic inhibition of mTOR improves lapatinib sensitivity in HER2-overexpressing breast cancer cells with primary trastuzumab resistance. Anticancer Agents Med Chem 2012;12(2):151-62
  • Garrett JT, Sutton CR, Kurupi R, et al. Combination of Antibody That Inhibits Ligand-Independent HER3 Dimerization and a p110alpha Inhibitor Potently Blocks PI3K Signaling and Growth of HER2+ Breast Cancers. Cancer Res 2013;73(19):6013-23
  • Schroder CP, Pedersen JV, Chua S, et al. Use of biomarkers and imaging to evaluate the treatment effect of AUY922, an HSP90 inhibitor, in patients with HER2+ or ER+ metastatic breast cancer. J Clin Oncol 2011;29(Suppl):e11024
  • He S, Acquaviva J, Friedland JC, et al. Inhibition of mTOR enhances the activity of HSP90 inhibitors in part through cessation of heat shock protein synthesis. Cancer Res 2013;73(8 Suppl 1):1038
  • PI3K Inhibitor BYL719 in combination with the HSP90 inhibitor AUY922 in patients with advanced or metastatic gastric cancer. Available from: www.clinicaltrials.gov/ct2/results?term=NCT01613950&Search=Search
  • Chatterjee M, Andrulis M, Stuhmer T, et al. The PI3K/Akt signaling pathway regulates the expression of Hsp70, which critically contributes to Hsp90-chaperone function and tumor cell survival in multiple myeloma. Haematologica 2013;98(7):1132-41
  • Anders CK, Carey LA. Biology, metastatic patterns, and treatment of patients with triple-negative breast cancer. Clin Breast Cancer 2009;9(Suppl 2):S73-81
  • Chacon RD, Costanzo MV. Triple-negative breast cancer. Breast Cancer Res 2010;12(Suppl 2):S3
  • Ibrahim YH, Garcia-Garcia C, Serra V, et al. PI3K inhibition impairs BRCA1/2 expression and sensitizes BRCA-proficient triple-negative breast cancer to PARP inhibition. Cancer Discov 2012;2(11):1036-47
  • Isakoff SJ. Triple-negative breast cancer: role of specific chemotherapy agents. Cancer J 2010;16(1):53-61
  • Szanto A, Hellebrand EE, Bognar Z, et al. PARP-1 inhibition-induced activation of PI-3-kinase-Akt pathway promotes resistance to taxol. Biochem Pharmacol 2009;77(8):1348-57
  • Saal LH, Holm K, Maurer M, et al. PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res 2005;65(7):2554-9
  • Kimbung S, Biskup E, Johansson I, et al. Co-targeting of the PI3K pathway improves the response of BRCA1 deficient breast cancer cells to PARP1 inhibition. Cancer Lett 2012;319(2):232-41
  • Juvekar A, Burga LN, Hu H, et al. Combining a PI3K inhibitor with a PARP inhibitor provides an effective therapy for BRCA1-related breast cancer. Cancer Discov 2012;2(11):1048-63
  • Dey N, Sun Y, Carlson J, et al. A combination of dual PI3K-mTOR inhibitor, GDC-0980, with PARP inhibitor plus carboplatin blocked tumor growth of BRCA-competent triple-negative breast cancer cells. J Clin Oncol 2013;31(15 Suppl):abstract 2613
  • Phase I of BKM120/Olaparib for triple negative breast cancer or high grade serous ovarian cancer. Available from: www.clinicaltrials.gov/ct2/results?term=NCT01623349&Search=Search
  • Grob TJ, Heilenkotter U, Geist S, et al. Rare oncogenic mutations of predictive markers for targeted therapy in triple-negative breast cancer. Breast Cancer Res Treat 2012;134(2):561-7
  • Mirzoeva OK, Das D, Heiser LM, et al. Basal subtype and MAPK/ERK kinase (MEK)-phosphoinositide 3-kinase feedback signaling determine susceptibility of breast cancer cells to MEK inhibition. Cancer Res 2009;69(2):565-72
  • Ibrahim YH, Serra V, Scaltriti M, et al. Combined PI3K and MEK inhibition in patient-derived xenografts generated from recurrent triple negative breast cancer. abstract 648 Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011
  • Safety, pharmacokinetics and pharmacodynamics of BKM120 plus MEK162 in selected advanced solid tumor patients. Available from: www.clinicaltrials.gov/ct2/results?term=NCT01363232&Search=Search
  • A study evaluating the safety, tolerability and pharmacokinetics of GDC-0973 in combination with GDC-0941 when administered in patients with locally advanced or metastatic solid tumors. Available from: www.clinicaltrials.gov/ct2/results?term=NCT00996892&Search=Search
  • LoRusso P, Shapiro G, Pandya SS, et al. 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. J Clin Oncol 2012;30(15 Suppl):abstract 2566
  • A study to investigate safety, pharmacokinetics (PK) and Pharmacodynamics (PD) of BKM120 Plus GSK1120212 in selected advanced solid tumor patients. Available from: www.clinicaltrials.gov/ct2/results?term=NCT01155453&Search=Search
  • Bedard P, Tabernero J, Kurzrock R, et al. A first-in-human phase 1b open-study multicenter, dose escalation study of the oral pan-PI3K inhibitor BKM120 in combination with the oral MEK1/2 inhibitor GSK1120212 in patients with selected advanced solid tumors. J Clin Oncol 2012;30(Suppl):abstract 3003
  • Kurzrock R, Patnaik A, Rosenstein L, et al. Phase I dose-escalation of the oral MEK1/2 inhibitor GSK1120212 (GSK212) dosed in combination with the oral AKT inhibitor GSK2141795 (GSK795). J Clin Oncol 2011;29(15 Suppl):abstract 3085
  • Trametinib and Akt Inhibitor GSK2141795 in treating patients with metastatic triple-negative breast cancer. Available from: www.clinicaltrials.gov/ct2/results?term=NCT01964924&Search=Search
  • Heist RS, Gandhi L, Shapiro G, et al. Combination of a MEK inhibitor, pimasertib (MSC1936369B), and a PI3K/mTOR inhibitor, SAR245409, in patients with advanced solid tumors: Results of a phase Ib dose-escalation trial. J Clin Oncol 2013;31(15 Suppl):abstract 2530
  • Infante JR, Gandi L, Shapiro G, et al. Combination of the MEK inhibitor, pimasertib (MSC1936369B), and the PI3K/mTOR inhibitor, SAR245409, in patients with advanced solid tumors: Results of a phase Ib dose-escalation trial. Cancer Res 2013;73(8 Suppl 1):abstract LB-147
  • Trial of MEK inhibitor and PI3K/mTOR inhibitor in subjects with locally advanced or metastatic solid tumors. Available from: www.clinicaltrials.gov/ct2/results?term=NCT01390818&Search=Search
  • Turner N, Lambros MB, Horlings HM, et al. Integrative molecular profiling of triple negative breast cancers identifies amplicon drivers and potential therapeutic targets. Oncogene 2010;29(14):2013-23
  • Andre F, Bachelot T, Campone M, et al. Targeting FGFR with dovitinib (TKI258): preclinical and clinical data in breast cancer. Clin Cancer Res 2013;19(13):3693-702
  • Issa A, Gill JW, Heideman MR, et al. Combinatorial targeting of FGF and ErbB receptors blocks growth and metastatic spread of breast cancer models. Breast Cancer Res 2013;15(1):R8
  • Kaufman P, Awada A, Twelves C. A phase III, open-label, randomized, multicenter study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with anthracyclines and taxanes. Cancer Res 2012;72(24 Suppl 8):abstract S6-6
  • Signature. Available from: www.signaturetrial.com
  • BKM120 for patients with PI3K-activated tumors. Available from: www.clinicaltrials.gov/ct2/results?term=NCT01833169&Search=Search
  • Ma C, Wang J, Luo J, et al. A phase 1 trial of BKM120, a novel oral selective phosphatidylinositol-3-kinase (PI3K) inhibitor, in combination with fulvestrant in postmenopausal women with estrogen receptor positive metastatic breast cancer. abstract PD1-4 Presented at 36th SABCS Annual Meeting; 2013
  • Munster PM, Hamilton EP, Franklin C, et al. Phase Ib study of LEE011 and BYL719 in combination with letrozole in estrogen receptor-positive, HER2-negative breast cancer (ER+, HER2– BC). ASCO Annual Meeting; 2014; Poster 533
  • Bardia A, Modi S, Chavez-MacGregor M, et al. Phase Ib/II study of LEE011, everolimus, and exemestane in postmenopausal women in ER+/HER2– metastatic breast cancer. ASCO Annual Meeting; 2014; Poster 535

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.