Aneuploidy sensitizes cells to SREBP-pathway inhibition in squamous cell carcinoma

Abstract Squamous cell carcinomas (SCCs) in the lung, head and neck, cervix, and esophagus are characterized by widespread chromosome-arm aneuploidies, most frequently recurrent 3q-gain. However, how these alterations influence cancer development and therapeutic vulnerabilities remains unclear. To identify aneuploidy-driven therapeutic targets, we performed genome-wide CRISPR interference (CRISPRi) and drug-repurposing screens in isogenic immortalized lung epithelial cells harboring chromosome 3-disomy or 3q-gain. Both screens converged on a mevalonate pathway dependency specific to 3q-gain cells, which exhibited heightened sensitivity to sterol regulatory element-binding protein (SREBP) disruption. Rescue experiments demonstrated that these vulnerabilities were on target and that pathway inhibition preferentially causes apoptosis in 3q-gain cells. Transcriptomic and lipidomic profiling revealed 3q-gain-associated alterations in SREBP activation, cholesterol and fatty-acid biosynthesis, and lipid composition. Perturbing SREBP signaling impaired viability in SCC cell lines and suppressed tumor growth in xenografts with 3q-gain. These findings identify an aneuploidy-driven, targetable vulnerability in SCC. Significance Here, we demonstrate that SCC-recurrent 3q-gain is a selective vulnerability to SREBP-pathway inhibition. We identify an aneuploidy-driven therapeutic liability in squamous tumors for lipid-targeted precision therapies, providing a framework for targeted treatment in SCC. Competing Interest Statement A.M.T. and M.M. received research support from Ono Pharmaceuticals for this work. M.M., A.M.T., and N.Z.K. are inventors of a patent application related to this work (WO/2025/255338). A.M.T. is an equity holder of Karyoverse. M.M. is an equity holder of, consultant for, and receives research support from Bayer, and receives patent royalties from Bayer and Labcorp. M.M. is also an equity holder of and consultant for Delve Bio, and an equity holder of Karyoverse and Isabl. M.M. has previously received research support from Janssen and Ono Pharmaceutical and has held equity and consulting roles with Foundation Medicine. B.H. has received institutional research funding from Genentech-Roche, NexImmune, and Johnson & Johnson; speaker honoraria from OncLive; and advisory board fees from AstraZeneca, Ideaya Biosciences, Jazz Pharmaceuticals, Sorrento Therapeutics, Regeneron, Bristol Myers Squibb, Genentech-Roche, Synthekine, Boehringer Ingelheim, and Bayer. All other authors declare no potential conflicts of interest. Footnotes Conflict of Interest: A.M.T. and M.M. received research support from Ono Pharmaceuticals for this work. M.M., A.M.T., and N.Z.K. are inventors of a patent application related to this work (WO/2025/255338). A.M.T. is an equity holder of Karyoverse. M.M. is an equity holder of, consultant for, and receives research support from Bayer, and receives patent royalties from Bayer and Labcorp. M.M. is also an equity holder of and consultant for Delve Bio, and an equity holder of Karyoverse and Isabl. M.M. has previously received research support from Janssen and Ono Pharmaceutical and has held equity and consulting roles with Foundation Medicine. B.H. has received institutional research funding from Genentech-Roche, NexImmune, and Johnson & Johnson; speaker honoraria from OncLive; and advisory board fees from AstraZeneca, Ideaya Biosciences, Jazz Pharmaceuticals, Sorrento Therapeutics, Regeneron, Bristol Myers Squibb, Genentech-Roche, Synthekine, Boehringer Ingelheim, and Bayer. All other authors declare no potential conflicts of interest.