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Ref Type Journal Article
PMID (37493631)
Authors Stanland LJ, Ang HX, Hoj JP, Chu Y, Tan P, Wood KC, Luftig MA
Title CBF-Beta Mitigates PI3K-Alpha-Specific Inhibitor Killing through PIM1 in PIK3CA-Mutant Gastric Cancer.
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Abstract Text PIK3CA is the second most mutated gene in cancer leading to aberrant PI3K/AKT/mTOR signaling and increased translation, proliferation, and survival. Some 4%-25% of gastric cancers display activating PIK3CA mutations, including 80% of Epstein-Barr virus-associated GCs. Small molecules, including pan-PI3K and dual PI3K/mTOR inhibitors, have shown moderate success clinically, due to broad on-target/off-tissue effects. Thus, isoform-specific and mutant selective inhibitors have been of significant interest. However, drug resistance is a problem and has affected success of new drugs. There has been a concerted effort to define mechanisms of resistance and identify potent combinations in many tumor types, though gastric cancer is comparatively understudied. In this study, we identified modulators of the response to the PI3Kα-specific inhibitor, BYL719, in PIK3CA-mutant GCs. We found that loss of NEDD9 or inhibition of BCL-XL conferred hypersensitivity to BYL719, through increased cell-cycle arrest and cell death, respectively. In addition, we discovered that loss of CBFB conferred resistance to BYL719. CBFB loss led to upregulation of the protein kinase PIM1, which can phosphorylate and activate several overlapping downstream substrates as AKT thereby maintaining pathway activity in the presence of PI3Kα inhibition. The addition of a pan-PIM inhibitor re-sensitized resistant cells to BYL719. Our data provide clear mechanistic insights into PI3Kα inhibitor response in PIK3CA-mutant gastric tumors and can inform future work as mutant-selective inhibitors are in development for diverse tumor types.Loss of either NEDD9 or BCL-XL confers hypersensitivity to PI3K-alpha inhibition whereas loss of CBFB confers resistance through a CBFB/PIM1 signaling axis.

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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
PIK3CA H1047R colorectal cancer resistant Alpelisib Preclinical - Cell culture Actionable In a preclinical study, a colorectal cancer cell line harboring PIK3CA H1047R was resistant to Piqray (alpelisib) in culture (PMID: 37493631). 37493631
PIK3CA E453K PIK3CA E545A stomach cancer sensitive Alpelisib + Dasatinib Preclinical - Cell culture Actionable In a preclinical study, the addition of Sprycel (dasatinib) to Piqray (alpelisib) treatment resulted in an increased inhibition of proliferation in a gastric cancer cell line harboring PIK3CA E545A and E453K in culture (PMID: 37493631). 37493631
PIK3CA E453K PIK3CA E545A stomach cancer sensitive Alpelisib Preclinical - Cell culture Actionable In a preclinical study, Piqray (alpelisib) inhibited growth and induced cell cycle arrest and inhibited phosphorylation of Akt and S6 in a gastric cancer cell line harboring PIK3CA E545A and E453K in culture (PMID: 37493631). 37493631
PIK3CA E545K stomach cancer sensitive Alpelisib Preclinical - Cell culture Actionable In a preclinical study, Piqray (alpelisib) inhibited growth and induced cell cycle arrest and inhibited phosphorylation of Akt and S6 in a gastric cancer cell line harboring PIK3CA E545K in culture (PMID: 37493631). 37493631
PIK3CA E545K stomach cancer sensitive A-1331852 + Alpelisib Preclinical - Cell culture Actionable In a preclinical study, the combination of Piqray (alpelisib) and A-1331852 synergistically inhibited viability in a gastric cancer cell line harboring PIK3CA E545K in culture (PMID: 37493631). 37493631
PIK3CA E453K PIK3CA E545A stomach cancer sensitive A-1331852 + Alpelisib Preclinical - Cell culture Actionable In a preclinical study, the combination of Piqray (alpelisib) and A-1331852 synergistically inhibited viability in a gastric cancer cell line harboring PIK3CA E545A and E453K in culture (PMID: 37493631). 37493631