CDK9 inhibition sensitizes intrinsically resistant BRAF V600E mutant colorectal cancer to BRAF inhibitors.

Recently, the BRAF inhibitor (Encorafenib) in combination with Cetuximab and mFOLFOX6 has been approved for the treatment of metastatic CRC (mCRC) patients with BRAF V600E mutation in the first line. However, intrinsic resistance to BRAFi still limits its therapeutic efficacy, and the clinical response is only ∼5%. One potential strategy to improve mCRC therapy is to combine agents that target key cellular signaling pathways, which may yield synergistic antitumor efficacy and overcome drug resistance. Herein, CDK9 inhibitors (CDK9i) were identified as candidate synergistic agents through kinase library-based high-throughput screening (HTS) and RNA sequencing. CDK9i synergistically sensitizes the therapeutic efficacy of BRAFi (as well as inhibitors of well-known downstream effector of BRAF, MEK and ERK) in multiple intrinsically resistant CRC models. Notably, CDK9i in combination with BRAFi also resulted in an enhanced therapeutic response in chemo-resistant CRC cells and PDOs. Taken together, CDK9 inhibition overcomes intrinsic resistance to BRAFi monotherapy, and targeting CDK9-mediated transcriptional elongation appears to be a promising and tolerable sensitization strategy for BRAFi-based treatment in mCRC, even in chemo-resistant mCRC.