Abstract 1880: Deconstructing the paradigm of oncogene cooperation: Targeting MYC to enhance response and overcome resistance to KRAS inhibitors.

Abstract Background: Activating mutations in KRAS, particularly at codon G12, are common in non-small cell lung cancer (NSCLC, ∼30%), pancreatic ductal adenocarcinoma (PDAC, ∼90%), and colorectal cancer (CRC, ∼35%). Although KRAS-G12C inhibitors (KRASi) such as sotorasib and adagrasib are approved for NSCLC, their clinical benefit is frequently limited by intrinsic and acquired resistance. MYC, a key transcription factor downstream of KRAS, is often deregulated in cancer and contributes to tumorigenesis and therapeutic resistance. Omomyc (OMO-103), the only direct MYC inhibitor currently in Phase II clinical trials, offers a unique opportunity to evaluate the impact of MYC blockade in KRAS-driven tumors. Methods: We used NSCLC, CRC, and PDAC tumor cell lines and patient-derived xenograft (PDX) models to characterize KRAS-dependent signaling and to assess the effects of KRASi, Omomyc, and their combination on proliferation, cell-cycle progression, and apoptosis. Mechanistic studies included Western blotting and RNA-seq analyses. Results: Dual KRAS and MYC inhibition synergistically impaired proliferation and induced robust apoptosis across models. Omomyc sensitized KRAS-mutant cells with intrinsic resistance to KRASi and restored drug responsiveness in models with acquired resistance. Transcriptomic and proteomic analyses revealed extensive reprogramming of oncogenic pathways upon combination therapy. In vivo, co-treatment with OMO-103 and KRASi resulted in significantly greater tumor regression than either monotherapy. Conclusions: These findings demonstrate critical cooperation between MYC and KRAS in driving tumor survival and resistance to KRAS inhibition. Direct MYC blockade enhances the therapeutic activity of KRAS inhibitors and represents a promising strategy to overcome both intrinsic and acquired resistance in multiple KRAS-mutant cancer types. Citation Format: Daniel Capitán-Leo, Íñigo González-Larreategui, Magda Arnal, Judit Grueso, Lorena Sansegundo-Barbosa, Hugo Thabussot, Irene Ferrer, Silvestre Vicent, Marie-Eve Beaulieu, Sílvia Casacuberta-Serra, Laura Soucek. Deconstructing the paradigm of oncogene cooperation: Targeting MYC to enhance response and overcome resistance to KRAS inhibitors 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 1880.