Pancreatic cancer is one of the deadliest forms of cancer, with median 5-year survival rates less than 10%. This disease is recalcitrant to chemotherapeutic approaches and recently approved therapies afford only modest improvements in survival. KRAS is the most commonly mutated gene in pancreatic tumors with an incidence rate exceeding 90%. Despite intensive efforts, KRAS has remained undruggable. Kinases acting both upstream and downstream of RAS continue to be exploited for the development of novel agents to attenuate signaling through this critical oncogene. While EGFR and MEK inhibitor monotherapies have been evaluated in the clinic for the treatment of pancreatic cancer, efficacy has been modest despite their relevance to MAP kinase (MAPK) pathway-altered tumors. Novel therapies are urgently needed to address adaptive signaling mechanisms that diminish the effectiveness of kinase-targeted approaches. MTX-211 is a first-in-class dual inhibitor of PI3K and EGFR kinase with a promising pharmaceutical profile and proven ability to potentiate the effectiveness of MEK inhibitor therapy in KRAS mutant colorectal tumors. The present study was undertaken to extend our evaluation of MTX-211 to include pancreatic cancer model systems. We have found that MTX-211 exhibits low micromolar potency against an extensive panel of primary models of pancreatic cancer and is highly synergistic with the MEK inhibitor trametinib. Preliminary data suggest that this synergy is driven by the ability of MTX-211 to target compensatory transcriptional activation of HER3 that occurs in response to MEK inhibition. A genetically engineered KRAS and p53 mutant (KPC) mouse model was transduced with a lentiviral construct encoding a caspase reporter, which was used to show that the combination of MTX-211 and trametinib elicited a significant increase in apoptosis over single agent controls. Results from an animal study conducted with the KPC model further showed that the combination of MTX-211 and trametinib significantly slowed growth of these aggressive tumors. Employing both KPC and patient-derived xenograft models of pancreatic cancer, efforts are underway to optimize therapeutic outcome in response to MTX-211-based combination treatment regimens.
Citation Format: Christy Frankowski-McGregor, Joel Maust, Elizabeth Ziemke, Rachel Mumby, Amy Delaney, Alnawaz Rehemtulla, Christopher Whitehead, Judith S. Sebolt-Leopold. MTX-211, a dual and selective inhibitor of EGFR and PI3 kinase, shows promising activity in combination with MEK inhibition in preclinical models of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2931.