Abstract

<div>Abstract<p><i>PIK3CA</i> 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 <i>PTEN</i> 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 <i>PTEN</i> loss and activating <i>AKT1</i> mutations. Notably, although secondary <i>PIK3CA</i> mutations were previously reported to increase sensitivity to PI3Kα inhibitors, we identified emergent secondary resistance mutations in <i>PIK3CA</i> 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 <i>PIK3CA</i>-mutated cancers.</p>Significance:<p>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 <i>PIK3CA</i> resistance mutations that can be overcome by an allosteric PI3Kα inhibitor.</p><p><i><a href="https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-23-1392" target="_blank">See related commentary by Gong and Vanhaesebroeck, p. 204</a></i>.</p><p><i><a href="https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-23-0944" target="_blank">See related article by Varkaris et al., p. 240</a></i>.</p><p><i><a href="https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-14-2-ITI" target="_blank">This article is featured in Selected Articles from This Issue, p. 201</a></i></p></div>

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