Abstract LB449: Strategies to overcome resistance to PI3Kalpha-selective inhibitors mediated by acquired alterations in the PI3K/AKT pathway

Abstract PIK3CA is among the most frequently mutated kinases in multiple types of cancer, including in 40% of hormone receptor-positive, HER2-negative breast cancers. The PI3Kα-selective orthosteric inhibitor alpelisib is the only drug targeting PIK3CA currently approved in this patient population, in combination with fulvestrant. As commonly observed with other targeted therapies, resistance often develops during treatment with PI3Kα-selective inhibitors. In one of the largest patient cohorts to date, including serial liquid biopsies and rapid autopsies in 39 patients, our group has observed genomic alterations within the PI3K/AKT pathway as one of the major mechanisms of resistance to these agents. Among them, we have identified for the first-time secondary mutations in PIK3CA (W780R and Q859K) that decrease the affinity of the PI3Kα-selective inhibitors alpelisib and inavolisib, leading to acquired resistance. Multiple small molecule inhibitors designed to suppress signaling through the PI3K/AKT axis are currently in pre-clinical development. These include AKT inhibitors, isoform-selective as well as pan-PI3K inhibitors, and a novel subclass of allosteric PI3Kα-selective inhibitors designed to preferentially inhibit both kinase (H1047R) and helical (E545K) domain mutant PI3Kα activity. We have introduced all the emergent alterations observed in our patient cohort into breast cancer models and screen how they modify the effect of a structurally diverse array of PI3K/AKT inhibitors. While some acquired mutations compromise the effect of specific drugs, we have determined that the W780R mutation could drive universal resistance to ATP-competitive PI3K inhibitors that bind the catalytic pocket. Importantly, vertical pathway inhibition or allosteric inhibition with pan-mutant-selective PI3Kα inhibitors such as RLY-2608 or STX-478 could overcome resistance induced by all emerging secondary PIK3CA mutations.Dose-limiting toxicity in the form of hyperglycemia, rash or gastrointestinal issues are common in patients treated with orthosteric PI3Kα inhibitors. While mutant selective PI3Kα inhibitors induce less adverse effects in patients, they have a decreased potency targeting wildtype PIK3CA. We have identified wildtype PIK3CA-mediated feedback pathway reactivation as a potential mechanism of resistance to this type of inhibitors. Our work suggests that combining orthosteric and allosteric PI3Kα inhibitors as well as downstream pathway deactivation with AKT inhibitors could result in an increased therapeutic index and delay the emergence of resistance in patients. This work provides an insightful characterization of the current knowledge on clinical acquired resistance to PI3Kα inhibitors and proposes a detailed strategy to overcome resistance mediated by most PI3K/AKT alterations described to date. Citation Format: Ferran Fece de la Cruz, Andreas Varkaris, Elizabeth E. Martin, Bryanna L. Norden, Nicholas Chevalier, Allison M. Kehlmann, Ignaty Leshchiner, Haley Barnes, Sara Ehnstrom, Parasvi Patel, Janice S. Kim, Haley Ellis, Ioannis Sanidas, Kayao T. Lau, Aditya Bardia, Laura M. Spring, Steven J. Isakoff, Jochen K. Lennerz, Gad Getz, Ryan B. Corcoran, Dejan Juric. Strategies to overcome resistance to PI3Kalpha-selective inhibitors mediated by acquired alterations in the PI3K/AKT pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB449.