Systematic Functional Characterization of Resistance to PI3K Inhibition in Breast Cancer.
PIK3CA (which encodes the PI3K alpha isoform) is the most frequently mutated oncogene in breast cancer. Small-molecule PI3K inhibitors have shown promise in clinical trials; however, intrinsic and acquired resistance limits their utility. We used a systematic gain-of-function approach to identify genes whose upregulation confers resistance to the PI3K inhibitor BYL719 in breast cancer cells. Among the validated resistance genes, Proviral Insertion site in Murine leukemia virus (PIM) kinases conferred resistance by maintaining downstream PI3K effector activation in an AKT-independent manner. Concurrent pharmacologic inhibition of PIM and PI3K overcame this resistance mechanism. We also observed increased PIM expression and activity in a subset of breast cancer biopsies with clinical resistance to PI3K inhibitors. PIM1 overexpression was mutually exclusive with PIK3CA mutation in treatment-naïve breast cancers, suggesting downstream functional redundancy. Together, these results offer new insights into resistance to PI3K inhibitors and support clinical studies of combined PIM/PI3K inhibition in a subset of PIK3CA-mutant cancers.



PIM kinase overexpression confers resistance to small-molecule PI3K inhibitors. Combined inhibition of PIM and PI3K may therefore be warranted in a subset of breast cancers. Cancer Discov; 6(10); 1134-47. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 1069.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.|The Broad Institute of MIT and Harvard, Cambridge, MA.|Division of Hematology Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston MA.
Xiuning
X
Le
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.|The Broad Institute of MIT and Harvard, Cambridge, MA.
Rajee
R
Antony
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, NewYork, NY.|Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
Pedram
P
Razavi
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.|The Broad Institute of MIT and Harvard, Cambridge, MA.
Daniel J
DJ
Treacy
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.|The Broad Institute of MIT and Harvard, Cambridge, MA.
Flora
F
Luo
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.|The Broad Institute of MIT and Harvard, Cambridge, MA.
Mahmoud
M
Ghandi
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, NewYork, NY.
Pau
P
Castel
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, NewYork, NY.|Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.
Maurizio
M
Scaltriti
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, NewYork, NY.|Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
Jose
J
Baselga
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.|The Broad Institute of MIT and Harvard, Cambridge, MA.|Department of Medicine, Brigham and Women's Hospital, Boston MA.
Levi A
LA
Garraway
D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics*; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051573:Proto-Oncogene Proteins c-pim-1 / Q000235:genetics*; D013844:Thiazoles / Q000494:pharmacology; D015854:Up-Regulation
D047428:Protein Kinase Inhibitors; D013844:Thiazoles; C585539:Alpelisib; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C496634:PIM1 protein, human; D051573:Proto-Oncogene Proteins c-pim-1