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Ref Type Journal Article
PMID (37623743)
Authors Buckbinder L, St Jean DJ, Tieu T, Ladd B, Hilbert B, Wang W, Alltucker JT, Manimala S, Kryukov GV, Brooijmans N, Dowdell G, Jonsson P, Huff M, Guzman-Perez A, Jackson EL, Goncalves MD, Stuart DD
Title STX-478, a Mutant-Selective, Allosteric PI3Kα Inhibitor Spares Metabolic Dysfunction and Improves Therapeutic Response in PI3Kα-Mutant Xenografts.
URL
Abstract Text Phosphoinositide 3-kinase α (PIK3CA) is one of the most mutated genes across cancers, especially breast, gynecologic, and head and neck squamous cell carcinoma tumors. Mutations occur throughout the gene, but hotspot mutations in the helical and kinase domains predominate. The therapeutic benefit of isoform-selective PI3Kα inhibition was established with alpelisib, which displays equipotent activity against the wild-type and mutant enzyme. Inhibition of wild-type PI3Kα is associated with severe hyperglycemia and rash, which limits alpelisib use and suggests that selectively targeting mutant PI3Kα could reduce toxicity and improve efficacy. Here we describe STX-478, an allosteric PI3Kα inhibitor that selectively targets prevalent PI3Kα helical- and kinase-domain mutant tumors. STX-478 demonstrated robust efficacy in human tumor xenografts without causing the metabolic dysfunction observed with alpelisib. Combining STX-478 with fulvestrant and/or cyclin-dependent kinase 4/6 inhibitors was well tolerated and provided robust and durable tumor regression in ER+HER2- xenograft tumor models.These preclinical data demonstrate that the mutant-selective, allosteric PI3Kα inhibitor STX-478 provides robust efficacy while avoiding the metabolic dysfunction associated with the nonselective inhibitor alpelisib. Our results support the ongoing clinical evaluation of STX-478 in PI3Kα-mutated cancers, which is expected to expand the therapeutic window and mitigate counterregulatory insulin release. See related commentary by Kearney and Vasan, p. 2313. This article is featured in Selected Articles from This Issue, p. 2293.

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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 E542K PIK3CA H1065L breast cancer sensitive STX-478 Preclinical - Pdx Actionable In a preclinical study, STX-478 inhibited tumor growth of a breast cancer patient-derived xenograft (PDX) model harboring PIK3CA E542K and H1065L (PMID: 37623743). 37623743
PIK3CA D350N PIK3CA H1047R Advanced Solid Tumor sensitive STX-478 Preclinical - Cell culture Actionable In a preclinical study, STX-478 inhibited viability of a cell line harboring PIK3CA H1047R and D350N in culture (PMID: 37623743). 37623743
PIK3CA K111R PIK3CA H1047R lung carcinoma sensitive STX-478 Preclinical - Cell line xenograft Actionable In a preclinical study, STX-478 inhibited viability in a lung carcinoma cell line harboring PIK3CA H1047R and K111R in culture, and inhibited tumor growth in a cell line xenograft model (PMID: 37623743). 37623743
PIK3CA E545K head and neck squamous cell carcinoma sensitive STX-478 Preclinical - Pdx Actionable In a preclinical study, STX-478 inhibited tumor growth of a head and neck squamous cell cancer patient-derived xenograft (PDX) model harboring PIK3CA E545K (PMID: 37623743). 37623743
PIK3CA P539R PIK3CA H1047R Advanced Solid Tumor sensitive STX-478 Preclinical - Cell culture Actionable In a preclinical study, STX-478 inhibited viability of a cell line harboring PIK3CA H1047R and P539R in culture (PMID: 37623743). 37623743
PIK3CA H1047L colon cancer sensitive STX-478 Preclinical - Cell line xenograft Actionable In a preclinical study, STX-478 inhibited viability in a colon cancer cell line harboring PIK3CA H1047L in culture, and inhibited tumor growth and induced tumor regression in a cell line xenograft model (PMID: 37623743). 37623743
PIK3CA H1047R Her2-receptor negative breast cancer sensitive STX-478 Preclinical - Pdx & cell culture Actionable In a preclinical study, STX-478 inhibited viability in an ESR1-positive, ERBB2 (HER2)-negative breast cancer cell line harboring PIK3CA H1047R in culture and inhibited tumor growth and induced tumor regression with high-dose STX-478 in a cell line xenograft model and inhibited tumor growth in a patient-derived xenograft (PDX) model (PMID: 37623743). 37623743
PIK3CA H1047R head and neck squamous cell carcinoma sensitive STX-478 Preclinical - Cell line xenograft Actionable In a preclinical study, STX-478 inhibited viability in head and neck squamous cell cancer cell lines harboring PIK3CA H1047R in culture, and inhibited tumor growth and induced tumor regression in a cell line xenograft model (PMID: 37623743). 37623743
PIK3CA H1047R Her2-receptor positive breast cancer sensitive STX-478 Preclinical - Cell line xenograft Actionable In a preclinical study, STX-478 inhibited viability in a hormone receptor-negative, ERBB2 (HER2)-positive breast cancer cell line harboring PIK3CA H1047R in culture, and inhibited tumor growth in a cell line xenograft model (PMID: 37623743). 37623743
PIK3CA E542K Her2-receptor positive breast cancer sensitive STX-478 Preclinical - Pdx Actionable In a preclinical study, STX-478 inhibited tumor growth of a ERBB2 (HER2)-positive breast cancer patient-derived xenograft (PDX) model harboring PIK3CA E542K (PMID: 37623743). 37623743