Concurrent inhibition of EGFR and KRAS synergistically suppresses cell growth and prevents ERK reactivation in KRASG12D-mutant PDAC

Abstract ID 91572 Poster Board 244 Abstract Text Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease that is projected to become the 2nd leading cause of cancer-related mortality by 2030, surpassing colorectal cancer deaths. Mutational activation of the KRAS oncogene is present in over 90% of PDAC cases. For nearly four decades, the KRAS small GTPase was deemed undruggable. Due to recent breakthroughs, inhibitors targeting the KRASG12C mutation are FDA-approved and various inhibitors targeting additional KRAS mutations are being evaluated in clinical trials. However, some patients do not respond to these treatments, and those that initially respond eventually relapse due to treatment-induced resistance. Many putatively identified resistance mechanisms converge on reactivation of serine/threonine kinases ERK1/2 (ERK), the terminal effector of the ERK MAPK pathway. In the context of KRASG12C-mutant colorectal cancer, recent literature supports that increased activation of the wild-type KRAS, NRAS, and HRAS isoforms drives resistance to direct KRASG12C-inhibition. However, very little is known about how pancreatic cancer cells will adapt to KRAS inhibitor treatment. Thus, we employed KRAS inhibitor-anchored CRISPR-Cas9 loss-of-function screens in multiple PDAC cell lines to identify genes that modulate sensitivity to KRAS inhibitors. We identified loss of epidermal growth factor receptor (EGFR) as a modulator of KRAS inhibition, thus suggesting that EGFR activity may drive treatment-induced relapse. Notably, EGFR is amplified and mutated in the circulating tumor DNA of patients who have acquired resistance to KRAS inhibition. Here, we evaluate the combination of clinical candidate MRTX1133, a selective KRASG12D inhibitor, with erlotinib, an FDA-approved drug that inhibits EGFR activity, in a panel of KRASG12D-mutant PDAC cell lines and spheroid models. We found that MRTX1133 transiently suppresses ERK activity, but ERK activity rebounds by 72 hours. However, the combination of MRTX1133 and erlotinib prevents ERK rebound and synergistically suppresses PDAC cell growth. Thus, our results suggest that EGFR-mediated reactivation of ERK signaling is a mechanism by which PDAC cells survive in the presence of direct KRAS inhibition. Our ongoing studies are investigating intrinsic versus acquired resistance in KRASG12D-mutant PDAC cell lines. In summary, MRTX1133/erlotinib represent one therapeutic combination that may have a clinical benefit to extend the efficacy of direct KRAS inhibitors and mitigate treatment-induced relapse in PDAC patients.