Cyclin-dependent kinase 9 inhibitors as oncogene signaling modulators in combination with targeted therapy for the treatment of colorectal cancer.

Background: Colorectal cancer (CRC) is the second deadliest cancer worldwide and new treatment options are urgently needed. Cyclin dependent kinase 9 (CDK9) promotes aberrant RNA transcription in cancer and is a promising target for cancer therapies.

Methods: Using CRC cell lines as well as newly established patient-derived organoid models of CRC, we studied the clinically promising CDK9 inhibitors (AZD4573, BAY1125152/VIP152/enitociclib, and NVP2) to determine their therapeutic potential. We investigated the efficacy and mechanisms of action through cell growth and cytotoxicity assays, RNAseq, immunoblotting, and IHC.

Results: We found CDK9 inhibitors to be highly potent against CRC, through suppression of proliferation and induction of apoptosis. Our results demonstrated CDK9 inhibitors to be broadly active against a set of CRC models derived from a diverse patient population. Our mechanistic studies showed significant suppression of the Mitogen-active protein kinase (MAPK) signaling pathway due to CDK9 inhibitor treatment, suggesting that CDK9 inhibitor efficacy could be enhanced when combined with MAPK pathway inhibitors. As proof-of-concept, we found that CDK9 inhibitors and MEK inhibitors could be combined to synergistically suppress CRC growth and survival.

Conclusions: CDK9 inhibitors show promising activity against patient-derived models of CRC. MAPK signaling is particularly suppressed by CDK9 inhibitors. Combining CDK9 inhibitors and targeted therapy against MAPK signaling pathway may be a viable strategy worthy of further investigation preclinically and clinically.