Abstract
This study investigates the transcriptional impact of Q901, a highly selective cyclin-dependent kinase 7 (CDK7) inhibitor in clinical development. Q901 primarily disrupted MYC and E2F-dependent transcription programs, down-regulating cell cycle control and DNA damage repair pathways. CDK7 binding at the promoter-proximal regions was markedly stabilized by Q901, leading to reduced occupancy of MYC, E2F, and RNA polymerase II (RNAPII). These findings offered a novel therapeutic strategy to enhance cancer susceptibility to topoisomerase I (TOP1) DNA-protein cross-links (TOP1-DPCs) induced by TOP1 inhibitors. Resistance to TOP1 inhibitors arises through activation of DNA repair pathways when elongating RNAPII encounters TOP1-DPCs. By suppressing RNAPII transition from initiation to elongation and DNA repair pathways, Q901 stabilizes TOP1-DPCs and sensitizes tumors to TOP1 inhibitors. Preclinical studies demonstrated enhanced tumor suppression when combining Q901 with TOP1 inhibitor–based antibody-drug conjugates (TOP1i-ADCs), highlighting its potential as a therapeutic option for cancers resistant to TOP1i-ADC therapy.