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Ref Type Journal Article
PMID (34544753)
Authors Song KW, Edgar KA, Hanan EJ, Hafner M, Oeh J, Merchant M, Sampath D, Nannini MA, Hong R, Phu L, Forrest WF, Stawiski E, Schmidt S, Endres N, Guan J, Wallin JJ, Cheong J, Plise EG, Lewis Phillips GD, Salphati L, Heffron TP, Olivero AG, Malek S, Staben ST, Kirkpatrick DS, Dey A, Friedman LS
Title RTK-Dependent Inducible Degradation of Mutant PI3Kα Drives GDC-0077 (Inavolisib) Efficacy.
Journal Cancer discovery
Vol 12
Issue 1
Date 2022 01
URL
Abstract Text PIK3CA is one of the most frequently mutated oncogenes; the p110a protein it encodes plays a central role in tumor cell proliferation. Small-molecule inhibitors targeting the PI3K p110a catalytic subunit have entered clinical trials, with early-phase GDC-0077 studies showing antitumor activity and a manageable safety profile in patients with PIK3CA-mutant breast cancer. However, preclinical studies have shown that PI3K pathway inhibition releases negative feedback and activates receptor tyrosine kinase signaling, reengaging the pathway and attenuating drug activity. Here we discover that GDC-0077 and taselisib more potently inhibit mutant PI3K pathway signaling and cell viability through unique HER2-dependent mutant p110a degradation. Both are more effective than other PI3K inhibitors at maintaining prolonged pathway suppression. This study establishes a new strategy for identifying inhibitors that specifically target mutant tumors by selective degradation of the mutant oncoprotein and provide a strong rationale for pursuing PI3Kα degraders in patients with HER2-positive breast cancer. SIGNIFICANCE: The PI3K inhibitors GDC-0077 and taselisib have a unique mechanism of action; both inhibitors lead to degradation of mutant p110a protein. The inhibitors that have the ability to trigger specific degradation of mutant p110a without significant change in wild-type p110a protein may result in improved therapeutic index in PIK3CA-mutant tumors.See related commentary by Vanhaesebroeck et al., p. 20.This article is highlighted in the In This Issue feature, p. 1.

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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 breast cancer sensitive GDC-0077 Preclinical - Cell line xenograft Actionable In a preclinical study, GDC-0077 treatment led to tumor regression in an ESR1 (ER)-positive breast cancer cell line xenograft model harboring PIK3CA E545K (PMID: 34544753). 34544753
PIK3CA E545K colon cancer sensitive Taselisib Preclinical - Cell culture Actionable In a preclinical study, Taselisib (GDC-0032) treatment led to decreased cell viability in a colon cancer cell line expressing PIK3CA E545K in culture (PMID: 34544753). 34544753
PIK3CA E545K colon cancer sensitive GDC-0077 Preclinical - Cell culture Actionable In a preclinical study, GDC-0077 treatment led to decreased cell viability in a colon cancer cell line expressing PIK3CA E545K in culture (PMID: 34544753). 34544753
PIK3CA H1047R colon cancer sensitive GDC-0077 Preclinical - Cell culture Actionable In a preclinical study, GDC-077 treatment led to decreased cell viability in a colon cancer cell line expressing PIK3CA H1047R in culture (PMID: 34544753). 34544753
PIK3CA H1047R colon cancer sensitive Taselisib Preclinical - Cell culture Actionable In a preclinical study, Taselisib (GDC-0032) treatment led to decreased cell viability in a colon cancer cell line expressing PIK3CA H1047R in culture (PMID: 34544753). 34544753
PIK3CA E545K colon cancer no benefit Pictilisib Preclinical - Cell culture Actionable In a preclinical study, Pictilisib (GDC-0941) treatment did not affect cell viability in a colon cancer cell line expressing PIK3CA E545K in culture (PMID: 34544753). 34544753
PIK3CA H1047R colon cancer no benefit Pictilisib Preclinical - Cell culture Actionable In a preclinical study, Pictilisib (GDC-0941) treatment did not affect cell viability in a colon cancer cell line expressing PIK3CA H1047R in culture (PMID: 34544753). 34544753