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Supplementary Tables S1 to S5 from Allosteric PI3Kα Inhibition Overcomes On-target Resistance to Orthosteric Inhibitors Mediated by Secondary PIK3CA Mutations

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posted on 2024-02-08, 08:20 authored by Andreas Varkaris, Ferran Fece de la Cruz, Elizabeth E. Martin, Bryanna L. Norden, Nicholas Chevalier, Allison M. Kehlmann, Ignaty Leshchiner, Haley Barnes, Sara Ehnstrom, Anastasia-Maria Stavridi, Xin Yuan, Janice S. Kim, Haley Ellis, Alkistis Papatheodoridi, Hakan Gunaydin, Brian P. Danysh, Laxmi Parida, Ioannis Sanidas, Yongli Ji, Kayao Lau, Gerburg M. Wulf, Aditya Bardia, Laura M. Spring, Steven J. Isakoff, Jochen K. Lennerz, Kathryn Del Vecchio, Levi Pierce, Ermira Pazolli, Gad Getz, Ryan B. Corcoran, Dejan Juric

Table S1: Eligibility Criteria. Table S2: Genomic alterations within the PIK3CA pathway and other documented alterations for this study. Table S3: VAF of EOT alterations. Table S4: Comparison of Acquired PIK3CA mutations based on baseline activating mutation. Table S5: Comparison of Acquired PIK3CA mutations based on number of baseline activating PIK3CA mutations.

Funding

DOD Prostate Cancer Research Program (PCRP)

Cancer Moonshot (Misión contra el Cáncer)

National Cancer Institute (NCI)

United States Department of Health and Human Services

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American Society of Clinical Oncology (ASCO)

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ARTICLE ABSTRACT

PIK3CA mutations occur in ∼8% of cancers, including ∼40% of HR-positive breast cancers, where the PI3K-alpha (PI3Kα)-selective inhibitor alpelisib is FDA approved in combination with fulvestrant. Although prior studies have identified resistance mechanisms, such as PTEN loss, clinically acquired resistance to PI3Kα inhibitors remains poorly understood. Through serial liquid biopsies and rapid autopsies in 39 patients with advanced breast cancer developing acquired resistance to PI3Kα inhibitors, we observe that 50% of patients acquire genomic alterations within the PI3K pathway, including PTEN loss and activating AKT1 mutations. Notably, although secondary PIK3CA mutations were previously reported to increase sensitivity to PI3Kα inhibitors, we identified emergent secondary resistance mutations in PIK3CA that alter the inhibitor binding pocket. Some mutations had differential effects on PI3Kα-selective versus pan-PI3K inhibitors, but resistance induced by all mutations could be overcome by the novel allosteric pan-mutant-selective PI3Kα-inhibitor RLY-2608. Together, these findings provide insights to guide strategies to overcome resistance in PIK3CA-mutated cancers. In one of the largest patient cohorts analyzed to date, this study defines the clinical landscape of acquired resistance to PI3Kα inhibitors. Genomic alterations within the PI3K pathway represent a major mode of resistance and identify a novel class of secondary PIK3CA resistance mutations that can be overcome by an allosteric PI3Kα inhibitor.See related commentary by Gong and Vanhaesebroeck, p. 204.See related article by Varkaris et al., p. 240.This article is featured in Selected Articles from This Issue, p. 201

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    Cancer Discovery

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    Liquid Biopsy

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