LAUSR

KRAS is mutationally activated in 95% of pancreatic ductal adenocarcinomas (PDAC) and essential for maintenance of PDAC tumorigenic growth. The recent clinical evaluation of inhibitors of one KRAS mutant (KRASG12C) supports the therapeutic value of direct targeting of KRAS for PDAC treatment. However, this mutant comprises less than 2% of KRAS mutations in PDAC. Therefore, we have evaluated direct inhibitors of the predominant KRAS mutations (G12D, G12V and G12R) in PDAC. Additionally, both innate and treatment-associated resistance mechanisms will limit the effectiveness of direct KRAS inhibitors. Genomic sequencing analyses of patients who relapsed on KRASG12C inhibitors suggest that reactivation of KRAS effector signaling comprises one major mechanism of resistance. We determined that activation of MEK-ERK but not AKT activation alone is sufficient to drive resistance to KRASG12C/D inhibitors. However, our recent clinical evaluation of direct ERK inhibition in PDAC found that toxicity limited the effectiveness of this therapeutic approach. These observations prompted our studies to complete a system-wide determination of the molecular mechanisms by which ERK signaling supports KRAS-dependent PDAC growth. First, we determined the KRAS-ERK regulated transcriptome, kinome, total proteome and phosphoproteome in KRAS-mutant PDAC. We identified KRAS-dependent gene signature (677 KRAS-dependent and 1,051 KRAS-suppressed genes) that diverged significantly from the classical Hallmark KRAS gene signature. We identified 5,117 ERK-dependent phosphosites on 2,252 proteins, of which 88% and 67%, respectively, were not previously associated with ERK. Second, since a major consequence of ERK signaling involves activation of MYC-regulated gene transcription, we also determined the MYC-dependent transcriptome (2,086 MYC-dependent and 2,403 MYC-suppressed genes) that include 80 protein kinases. Together, these analyses define a highly complex and dynamic ERK-regulated signaling network that deregulates cell cycle progression, RHO GTPase function and metabolism to support KRAS-dependent PDAC growth. Citation Format: Channing J. Der. Targeting the ERK-MYC signaling network for the treatment of KRAS-mutant cancers [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr IA06.