Data from Allosteric PI3Kα Inhibition Overcomes On-target Resistance to Orthosteric Inhibitors Mediated by Secondary <i>PIK3CA</i> Mutations

• DOI: 10.1158/2159-8290.c.7065313.v1
• Publication Date: 2024-02-08T08:59:30Z
• Authors: Andreas Varkaris; Ferran Fece de la...; Elizabeth E. Martin; Bryanna L. Norden; Nicholas Chevalier; Allison M. Kehlmann; Ignaty Leshchiner; Haley Barnes; Sara Ehnstrom; Anastasia-Maria S...; Xin Yuan; Janice S. Kim; Haley Ellis; Alkistis Papatheo...; 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

&lt;div&gt;Abstract&lt;p&gt;&lt;i&gt;PIK3CA&lt;/i&gt; mutations occur in ∼8% of cancers, including ∼40% HR-positive breast where the PI3K-alpha (PI3Kα)-selective inhibitor alpelisib is FDA approved combination with fulvestrant. Although prior studies have identified resistance mechanisms, such as &lt;i&gt;PTEN&lt;/i&gt; loss, clinically acquired to PI3Kα inhibitors remains poorly understood. Through serial liquid biopsies and rapid autopsies 39 patients advanced cancer developing inhibitors, we observe that 50% acquire genomic alterations within PI3K pathway, loss activating &lt;i&gt;AKT1&lt;/i&gt; mutations. Notably, although secondary &lt;i&gt;PIK3CA&lt;/i&gt; were previously reported increase sensitivity emergent alter binding pocket. Some had differential effects on PI3Kα-selective versus pan-PI3K but induced by all could be overcome novel allosteric pan-mutant-selective PI3Kα-inhibitor RLY-2608. Together, these findings provide insights guide strategies &lt;i&gt;PIK3CA&lt;/i&gt;-mutated cancers.&lt;/p&gt;Significance:&lt;p&gt;In one largest patient cohorts analyzed date, this study defines clinical landscape inhibitors. Genomic pathway represent a major mode identify class can an inhibitor.&lt;/p&gt;&lt;p&gt;&lt;i&gt;&lt;a href="https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-23-1392" target="_blank"&gt;See related commentary Gong Vanhaesebroeck, p. 204&lt;/a&gt;&lt;/i&gt;.&lt;/p&gt;&lt;p&gt;&lt;i&gt;&lt;a href="https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-23-0944" article Varkaris et al., 240&lt;/a&gt;&lt;/i&gt;.&lt;/p&gt;&lt;p&gt;&lt;i&gt;&lt;a href="https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-14-2-ITI" target="_blank"&gt;This featured Selected Articles from This Issue, 201&lt;/a&gt;&lt;/i&gt;&lt;/p&gt;&lt;/div&gt;