Abstract PR005: <i>KRAS</i> amplification as <i>de novo</i> oncogenic alteration and therapeutic target in human cancers

Abstract KRAS mutations are established oncogenic drivers and resistance mechanisms, but the biological and clinical significance of KRAS gene amplification (KRASAMP) is poorly understood. Here, we integrate genomic, structural, clinical, and functional data to show that KRASAMP is a recurrent de novo driver alteration and therapeutic vulnerability across human cancers. In three independent clinico-genomic datasets totaling 685,507 tumors, KRASAMP occurred in ∼2-3% of cancers, with enrichment in esophagogastric, germ cell, ovarian, non-small cell lung, colorectal, biliary tract, pancreatic, and breast cancers. High-level KRASAMP was largely mutually exclusive with canonical oncogenic drivers, and increasing KRAS copy number inversely correlated with the prevalence of alternative drivers, supporting KRASAMP as an independent oncogenic event. KRAS copy gains tightly correlated with increased KRAS mRNA and protein expression and with poorer overall survival across tumor types, irrespective of KRAS mutation status. Whole-genome sequencing and FISH revealed heterogeneous amplicon architectures, including extrachromosomal DNA and linear chromosomal configurations. In Rasless cells, forced overexpression of wild-type KRAS alone restored MAPK signaling, rescued proliferation, and conferred sensitivity to the mutation-agnostic pan-RAS inhibitor RMC-7977. These data establish KRAS amplification as a de novo, targetable oncogenic driver in human cancer. Citation Format: Mark M. Awad, Biagio Ricciuti, Sandra Vietti Michelina, Edoardo Garbo, Paolo Tarantino, Alok Tewari, Igor Odintsov, Xinan Wang, Cassio Murilo Trovo Hidalgo Filho, Nishant Gandhi, Kenneth Kehl, Giuseppe Lamberti, Alessandro Di Federico, Malini Gandhi, Federica Pecci, Mihaela Aldea, Valentina Santo, Eleonora Gariazzo, Lynette Sholl, Stefano Scalera, Marcello Maugeri, Nancy Lin, Federico Cappuzzo, Pasi Janne, Steven Ressler, Marzia Capelletti, Alexa Schrock, Toni Choueiri, Julie Wiese, Debbie Liao, Shailaja Kasibhatla, Sara Tolaney, Andrew Aguirre, Alice Shaw, Chiara Ambrogio. KRAS amplification as de novo oncogenic alteration and therapeutic target in human cancers [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_1):Abstract nr PR005.