Abstract IA08: Drugging undruggable kras: will myc do the trick?

Abstract

Abstract KRAS oncogene mutations are found in ~95% of pancreatic ductal adenocarcinoma (PDAC) and are well validated drivers of PDAC initiation and maintenance. Consequently, a major goal for the field is the development of effective anti-KRAS therapies. However, despite more than three decades of intensive effort, no effective pharmacologic inhibitors of the KRAS have reached the clinic, prompting the widely held perception that KRAS is “undruggable”. However, with more advanced knowledge of KRAS function and new technological approaches, there is renewed hope that the time is ripe to revisit targeting KRAS. I will present our studies focused on the RAF-MEK-ERK mitogen-activated protein kinase cascade. This effector signaling network is a well-validated driver of KRAS-dependent cancer growth. Despite this key role, pharmacologic inhibitors of RAF and MEK have been ineffective in inhibiting growth of KRAS-mutated cancers, in large part due to dynamic signal reprogramming leading to ERK reactivation and bypass of inhibitor action. We therefore addressed whether direct ERK inhibition may be a more effective therapeutic approach. We identified a growth suppression mechanism due to pharmacologic inhibition of ERK that involves degradation of the MYC oncoprotein, activation of the p16INK4A-RB1 tumor suppressor pathway and induction of a senescence-like phenotype. We also applied unbiased genetic and chemical functional screens, as well as reverse phase protein array analyses, and identified the PI3K-AKT-mTOR signalling network as a key driver of pancreatic cancer resistance to ERK inhibition. Novel combination inhibitor approaches that synergistically enhanced ERK inhibitor anti-tumor activity were also identified. Finally, we determined that continued expression of KRAS was required for maintenance of MYC protein expression. We determined that previously identified mechanisms of RAS effector signaling alone did not account for MYC protein regulation in PDAC, prompting our search for novel protein kinases that regulate MYC protein degradation. Our efforts are centered defining pharmacologic strategies to accelerate MYC protein degradation as a novel approach for blocking mutant KRAS in PDAC. Citation Format: Channing J. Der.{Authors}. Drugging undruggable kras: will myc do the trick? [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr IA08.