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|Ref Type||Journal Article|
|Authors||Le X, Antony R, Razavi P, Treacy DJ, Luo F, Ghandi M, Castel P, Scaltriti M, Baselga J, Garraway LA|
|Title||Systematic Functional Characterization of Resistance to PI3K Inhibition in Breast Cancer.|
|Abstract Text||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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|AKT1 over exp PIK3CA H1047R||breast cancer||resistant||Alpelisib||Preclinical - Cell culture||Actionable||In a preclinical study, Akt1 over expression in breast cancer cells harboring PIK3CA H1047R resulted in resistance to Alpelisib (BYL719) in culture (PMID: 27604488).||27604488|
|AKT1 over exp PIK3CA E545K||breast cancer||resistant||Pictilisib||Preclinical - Cell culture||Actionable||In a preclinical study, Akt1 over expression in breast cancer cells harboring PIK3CA E545K resulted in resistance to Pictilisib (GDC-0941) in culture (PMID: 27604488).||27604488|