Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Cancer discovery	12	1	2022 01	204-219	Cancer Discov

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	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 H1047R	colon cancer	sensitive	Inavolisib	Preclinical - Cell culture	Actionable	In a preclinical study, Itovebi (inavolisib) 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 E545K	breast cancer	sensitive	Inavolisib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Itovebi (inavolisib) treatment led to tumor regression in an ESR1 (ER)-positive breast cancer cell line xenograft model harboring PIK3CA E545K (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	sensitive	Inavolisib	Preclinical - Cell culture	Actionable	In a preclinical study, Itovebi (inavolisib) treatment led to decreased 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