Mechanisms of action and therapeutic targeting of the CARM1-NFIB axis in small cell lung cancer

ABSTRACT Treatment options for small cell lung cancer (SCLC) patients have remained largely unchanged for 3 decades, with no new FDA-approved treatments for 20 years, and no targeted therapies. We recently performed a screen for targets of an arginine methyltransferase called CARM1 and identified the NFI family of transcription factors as substrates for this PRMT. Importantly, NFIB harbors both oncogenic and metastatic promoting activities in the context of SCLC development. We confirmed that CARM1 functions as a transcriptional coactivator for NFIB. Based on these finding, we hypothesize that CARM1 methylation of NFIB is critical for its tumor-promoting functions. To further support this premise, we have generated a Nfib knockin mouse that harbors a R-to-K mutation in the CARM1 methylation site. When this mouse is crossed onto a SCLC genetically engineered mouse model (GEMM) the life expectancy of these mice is lengthened by a third (from 200 to 300 days), which is almost identical to the impact of Carm1-loss in the same GEMM. These finding raise the possibility of targeting SCLC with CARM1 small molecule inhibitors. We have also identified an effector molecule (TRIM29) for the CARM1 methylation site on NFIB. In this proposal we plan to: (1) perform a deep mechanistic analysis of this newly discovered CARM1/NFIB/TRIM29 signaling axis, and (2) investigate the therapeutic potential of targeting this axis using a battery of pre-clinical mouse models.