Characterization of KRAS-driven NSCLC cell lines with diverse mutational landscape and assessment of their response to MYC inhibition

Introduction: Lung cancer is the second most common type both in males and females leading cause of death worldwide. Inside lung cancer, Non-Small-Cell Cancer (NSCLC) represents around 85% cases, where KRAS mutated oncogene (∼25%) confers poor prognosis a high risk tumor recurrence. Subsets mutant NSCLC have been described based on presence concurrent mutations suppressor genes (TSGs), being TP53, KEAP1 LKB1 (also called STK11). Their mutation frequency noteworthy negatively affects survival response to treatments, especially immunotherapies (IO). The MYC key transcription factor downstream it usually amplified or deregulated majority NSCLC, not only promoting progression but also orchestrating immune evasion resistance IO, all features that make promising target these specific tumors. Although was long considered undruggable, our lab has designed first direct inhibitor, Omomyc. Here, we aim determine how different TSGs affect network KRAS-mutated context study their impact Omomyc mini-protein, which offers pharmacological approach inhibit KRAS-driven NSCLC. Methodology: We used Adenocarcinoma (KLA) isogenic cell lines modified by CRISPR/Cas9 technology order obtain knockout for TRP53, STK11 gene. MAX levels were determined western blot (WB) sensitivity proliferation metabolic assays. For vivo studies, cells injected subcutaneously into C57BL/6J hybrid F1 mice obtained from crossing C57BL/6 129/Sv strains. Results: basal increased compared parental one. KEAP1-deficient showed slower vitro growth, they presented faster KLA-STK11, often did give rise tumors syngeneic mice. change strain × provided better model KLA lines, able grow while maintaining other TSGs-mutant differences. Importantly, significantly reduced growth changed cycle profile lines. Even more remarkably, systemic inhibition displayed therapeutic efficacy microenvironment Conclusions: Loss increases context. Independently levels, respond similar extent inhibition. Thus, could provide potential Conflict interest: Ownership: L. Soucek M.E. Beaulieu are co-founders Peptomyc S.L. Board Directors: members BoD Corporate-sponsored Research: S.Vicent discloses receiving research funding Roche Revolution Medicines. None disclosed information applies current project. Other Substantive Relationships: S. Martínez-Martín, López, H. Thabussot, Beaulieu, Casacuberta-Serra employees shareholders