Abstract 4738: Pharmacological activation of PI3Kα triggers cancer cell death under metabolic stress

Abstract Cancer cells maintain oncogenic signalling within a survival “fitness zone”. While conventional targetαed therapies suppress this signalling below a critical threshold, excessive activation of the same pathways can also be lethal to cell, an observation currently being explored as a novel therapeutic approach in cancer. In this study, we report that hyperactivation of PI3Kα, one of the most frequently oncogenically activated PI3K isoforms, using the small-molecule PI3Kα activator UCL-TRO-1938 (further referred to as 1938) induces cytotoxicity in cancer cell lines while sparing non-transformed cells. This PI3K activation-induced cell death (PI3K-AICD) depends on AKT/mTORC1 activity, only occurs under serum starvation and is enhanced by low O2 levels. This hyperactivation lethality is mechanistically linked to an irreconcilable metabolic conflict by simultaneously activating anabolic PI3K/mTORC1 signalling in a catabolic (hypoxic) state, resulting in an unresolvable energy crisis and ultimately cell death. In serum-deprived lung cancer cell lines, 1938 induces a magnified endoplasmic reticulum stress response which, along with PI3K-AICD, can be mitigated by supplementation with unsaturated fatty acids, suggesting a critical metabolic dependency on lipid metabolism for driving this cell death response. Consequently, co-treatment with 1938 and inhibitors of stearoyl-CoA desaturase-1 (SCD1), an O2-dependent enzyme essential for fatty acid desaturation, amplifies the PI3K-AICD response. In summary, these findings demonstrate that enhancing an oncogenic pathway central to metabolic control can selectively kill cancer cells. Citation Format: Benoit Bilanges, Ralitsa Madsen, Daniele Morelli, Thomas Jones, Wayne Pearce, Etienne Leveille, Mustafa Kocak, Eden Bramson, Mark Bekala, Roger Williams, Nicholas McGranahan, Markus Muschen, William R. Sellers, Henning Walczak, Bart Vanhaesebroeck. Pharmacological activation of PI3Kα triggers cancer cell death under metabolic stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4738.