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Significance There have been FDA-approved anti-hedgehog drugs for treating hedgehog-driven cancers, which act by antagonizing the upstream component smoothened; however, resistance to smoothened inhibitor (SMOi) drugs have been described. Our previous study demonstrates that epigenetic or transcriptional targeted therapy represents an anti-hedgehog therapeutic strategy that can effectively overcome SMOi resistance. Here we report that transcriptional inhibition through targeting CDK7 suppresses the aberrant hedgehog pathway and growth of hedgehog-driven cancers either responsive or resistant to SMOi drugs, supporting CDK7 inhibition as a promising therapeutic strategy for overcoming SMOi resistance. Since multiple CDK7-targeted drugs have recently entered phase I trial for tumor therapy, our study provides the preclinical rationale for enrolling hedgehog-driven cancers into those clinical trials in the near future.

CDK7 inhibition suppresses aberrant hedgehog pathway and overcomes resistance to smoothened antagonists