Abstract
Medulloblastoma (MB) is the most frequent malignant childhood brain cancer and Group 3 MB (G3-MB) has the worst prognosis among the four consensus molecular subtypes. In G3-MB, MYC and OTX2 have been shown to be the oncogenic drivers and master transcriptional factors that tumor cells are highly addicted to, thereby serving as promising drug targets. Here we identified a covalent CDK7 inhibitor (CDK7i) THZ1 as the top potent inhibitor against tumor cell viability and transcription of MYC and OTX2 by a screening of epigenetic or transcription targeted small-molecule compounds against G3-MB cells. We further confirmed that G3-MB are highly sensitive to transcription inhibition through targeting CDK7. We showed that antagonizing CDK7 by either small-molecule inhibitor THZ1 or genetic approaches result in effective suppression of multiple patient-derived G3-MB tumor models both in vitro and in vivo. Mechanistically, THZ1 treatment preferentially inhibits the transcription of MYC and OTX2, resulting in massive suppression of their downstream oncogenic transcriptional programs and associated cancer transcriptional dependencies. We also uncovered a potential acquired THZ1-resistance mediated by upregulated ATP-binding cassette (ABC) family transporters in G3-MB and further reveal the combinatory synergy of THZ1 with BET inhibitor or HDAC inhibitor on suppressing G3-MB could be effective for overcoming such resistance. Together, our results demonstrate transcription inhibition by targeting CDK7 as a promising therapeutic strategy against the most aggressive form of MB. Since CDK7i drugs have entered phase I clinical trials against cancer already, our data provide rationale for opening CDK7i clinical trials for children with this aggressive cancer in near future.