Reference Detail

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer research : MCR	21	11	2023 Nov 01	1148-1162	Mol Cancer Res

URL

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 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	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 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
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 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 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