Unraveling the CDK9/PP2A/ERK network in transcriptional pause release and complement activation in KRAS-mutant cancers (MIA PaCa-2 )

KRASG12C inhibitors (KRASG12Ci) AMG510 and MRTX849 have shown promising efficacy in clinical trials and been approved for the treatment of KRASG12C-mutant cancers. However, the emergence of therapy-related drug resistance limits their long-term potential. We measured gene expression using RNA-sequencing for pancreatic cancer cell line MIA PaCa-2 parental and their AMG510-resistant equivalent without treatment or treated with with G12C KRAS inhibitor AMG510. AMG510-resistant MIA PaCa-2 cell line were generated from parental cell line by continuous dose escalation from as low as 1nM to 10μM. Once resistance to AMG510 was confirmed, both parental and resistant cell lines were treated with DMSO or AMG510. Gene expression analyses of these samples were performed.