Effect of PRMT5i (MRTX1719), ERKi (Adagrasib), RAFi (Belvarafenib) and their combination on non-small cell lung cancer cell line (LU99)
CDKN2A/MTAP co-deletion occurs frequently in non-small cell lung cancer and other solid tumors including glioblastoma and pancreatic ductal adenocarcinoma. Lung cancer remains the leading cause of cancer-related mortalities and fewer than 15% of glioblastoma or pancreatic cancer patients survive 5 years underscoring the need for more effective therapies. PRMT5 is a synthetic-lethal dependency in MTAP null tumors and an attractive therapeutic target for CDKN2A/MTAP deleted cancers. A new revolutionary class of inhibitors, referred to as MTA-cooperative PRMT5 inhibitors, has shown promising results in ongoing early phase clinical trials. Nonetheless, effective cancer treatment typically requires therapeutic combinations to improve response rates and defeat emergent resistant clones. Thus, we sought to determine whether perturbation of other pathways could improve the efficacy of MTA-cooperative PRMT5 inhibitors. Using a paralog and single gene targeting CRISPR library we screened MTAP deleted cancers in the presence or absence of PRMT5 inhibitors. We identified several genes sensitizing to PRMT5 inhibition including members of the MAP kinase pathway. We demonstrate that genetic depletion or chemical inhibition of MAP kinase pathway members using KRAS, MEK, ERK, and RAF inhibitors synergize with PRMT5 inhibition to kill CDKN2A/MTAP null, RAS-active tumors. Further, PRMT5 inhibitors combined with either KRAS or RAF inhibitors durable in vivo complete responses, emphasizing the potential benefit for patients. Overall design: 3 biological samples per condition were used, for a total of 18 samples: 3 replicates treated with DMSO, 3 replicates treated with PRMT5i (MRTX1719), 3 replicated treated with ERKi (Adagrasib), 3 replicates treated with RAFi (Belvarafenib), 3 replicates treated with PRMT5i+RAFi and 3 replicates treated with PRMT5i+ERKi