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

• DOI: 10.1124/jpet.244.915720
• Publication Date: 2024-05-13T22:53:12Z
• Authors: Amber Amparo; Grace Goodhart; Syed Ahmad; Andrew Waters
• Keywords: HRAS; EGFR Inhibitors

<b>Abstract ID 91572</b> <b>Poster Board 244</b> Text</b> Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease that projected to become the 2^nd leading cause of cancer-related mortality by 2030, surpassing colorectal cancer deaths. Mutational activation <i>KRAS</i> oncogene present in over 90% PDAC cases. For nearly four decades, KRAS small GTPase was deemed undruggable. Due recent breakthroughs, inhibitors targeting KRAS^G12C mutation are FDA-approved and various additional mutations being evaluated clinical trials. However, some patients do not respond these treatments, those initially eventually relapse due treatment-induced resistance. Many putatively identified resistance mechanisms converge on reactivation serine/threonine kinases ERK1/2 (ERK), terminal effector ERK MAPK pathway. In context KRAS^G12C-mutant cancer, literature supports increased wild-type KRAS, NRAS, HRAS isoforms drives direct KRAS^G12C-inhibition. very little known about how pancreatic cells will adapt inhibitor treatment. Thus, we employed inhibitor-anchored CRISPR-Cas9 loss-of-function screens multiple cell lines identify genes modulate sensitivity inhibitors. We loss epidermal growth factor receptor (EGFR) as modulator inhibition, thus suggesting EGFR activity may drive relapse. Notably, <i>EGFR</i> amplified mutated circulating tumor DNA who have acquired inhibition. Here, evaluate combination candidate MRTX1133, selective KRAS^G12D inhibitor, with erlotinib, an drug inhibits activity, panel KRAS^G12D-mutant spheroid models. found MRTX1133 transiently suppresses but rebounds 72 hours. erlotinib prevents rebound synergistically growth. our results suggest EGFR-mediated signaling mechanism which survive presence Our ongoing studies investigating intrinsic versus lines. summary, MRTX1133/erlotinib represent one therapeutic benefit extend efficacy mitigate patients.