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Ref Type Journal Article
PMID (37916958)
Authors Varkaris A, Fece de la Cruz F, Martin EE, Norden BL, Chevalier N, Kehlmann AM, Leshchiner I, Barnes H, Ehnstrom S, Stavridi AM, Yuan X, Kim JS, Ellis H, Papatheodoridi A, Gunaydin H, Danysh BP, Parida L, Sanidas I, Ji Y, Lau K, Wulf GM, Bardia A, Spring LM, Isakoff SJ, Lennerz JK, Pierce L, Pazolli E, Getz G, Corcoran RB, Juric D
Title Allosteric PI3K-alpha inhibition overcomes on-target resistance to orthosteric inhibitors mediated by secondary PIK3CA mutations.
Journal Vol Issue Date Pages Journal Short Title
Cancer discovery 2023 Nov 02 Cancer Discov
URL
Abstract Text PIK3CA mutations occur in ~8% of cancers, including ~40% of HR-positive breast cancers, where the PI3K-alpha (PI3Ka)-selective inhibitor alpelisib is FDA-approved in combination with fulvestrant. Although prior studies have identified resistance mechanisms, such as PTEN loss, clinical acquired resistance to PI3Ka inhibitors remains poorly understood. Through serial liquid biopsies and rapid autopsies in 39 patients with advanced breast cancer developing acquired resistance to PI3Ka-inhibitors, we observe that 50% of patients acquire genomic alterations within the PI3K-pathway, including PTEN loss and activating AKT1 mutations. Notably, while secondary PIK3CA mutations were previously reported to increase sensitivity to PI3Ka-inhibitors, we identified emergent secondary resistance mutations in PIK3CA that alter the inhibitor binding pocket. Some mutations had differential effects on PI3Ka-selective vs. pan-PI3K inhibitors, but resistance induced by all mutations could be overcome by the novel allosteric pan-mutant-selective PI3Ka-inhibitor RLY-2608. Together, these findings provide insights to guide strategies to overcome resistance in PIK3CA-mutated cancers.

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