Combination of PARP and KRAS G12D Inhibitors Enhances Efficacy of Therapeutic Vulnerabilities

To elucidate the molecular basis of the HR deficiency induced by KRASG12D inhibition, we conducted RNA sequencing (RNA-seq) on KRASG12D -mutant PDAC cells (AsPC-1, PANC-1, SW1990) treated with MRTX1133 and KRASG12V -mutant CFPAC-1 cell treated with pan-KRAS inhibitor BI-2865. To futher verified the molecular alternation, we also conducted RNA-seq on KRASG12D-mutant Patient-derived xenograft treated with MRTX1133. Overall design: For cell lines, AsPC-1, PANC-1, SW1990, and CFPAC-1 cells were cultured in duplicate in 10-cm dishes. The cells were either left untreated or treated with 50 nmol/L MRTX1133(AsPC-1, PANC-1, SW1990) or 100 nmol/L BI-2865 (CFPAC-1). Cells were collected 24 hours after treatment. For tumor tissue, tumor tissue from mice bearing pancreatic PDX in vehicle group and combination treatment group(Olaparib and MRTX1133) were collected after endpoint.