Abstract 5977: Evaluation of the potential combination regimens for q901, a clinical stage selective cdk7 inhibitor, as a DNA damage repair inhibitor

Background; Q901 is an extremely selective CDK7 inhibitor with potent single agent activity in the multiple in vivo tumor models including small cell lung cancer, cholangiocarcinoma, colon cancer, pancreatic cancer, hormone receptor positive breast cancer, castrate-resistant prostate cancer, and ovarian cancer. Q901 is currently in Phase 1/2 clinical trial for patients with selected advanced solid tumors (ClinicalTrials.gov: NCT05394103). In the preclinical models, Q901 treatment induces DNA damage response (DDR) impairment markers, particularly ones involved in the double-strand break repair mechanisms. This opens up broad range of possibilities for new combination regimen that could benefit from the accumulated DNA damages caused by Q901 treatment. Methods: Various combinations have been tested to evaluate potential clinical regimens in multiple solid tumor models. Two different BRCA wild-type ovarian cancer A2780 and OVCAR3 models, an estrogen receptor positive MCF7 breast cancer model, or a syngeneic RENCA mouse renal cancer model was tested with Q901 in combination with poly ADP-ribose polymerase (PARP) inhibitor, selective estrogen receptor degrader (SERD), an estrogen receptor (ER) PROTAC degrader, or an anti-PD-1 antibody, respectively. Results: In the A2780 model, the PARPi alone group showed 15% TGI (tumor growth inhibition), but significant tumor regression (104% TGI) was observed in the Q901 and PARPi combination. In the OVCAR3 model, the Q901 and PARPi combination group showed 105% TGI, whereas the PARPi alone group showed 38% TGI. In the MCF7 model, SERD alone showed 64% TGI and Q901 combination with SERD showed 94% TGI. Remarkable tumor regression (111% TGI) was observed in the MCF7 model combining ER PROTAC and Q901, whereas ER PROTAC alone group showed 55% TGI. In the RENCA model, the anti-PD-1 antibody alone group showed 13.2% TGI and the combination of Q901 and anti-PD-1 antibody showed 66% TGI. In summary, these preclinical model studies demonstrated significant additive/synergistic effects of the Q901 combination on tumor growth inhibition. Conclusion: The non-clinical data demonstrate that Q901 not only has a potential as a single agent,but can also be used in combination with other therapeutic strategies to develop next-generation cancer therapeutics to potentially address unmet medical needs. Citation Format: Donghoon Yu, Yeejin Jeon, YoonJi Lee, Seung-Joo Lee, Jaeseung Kim, Hyerim Jung, Tae-Kyung Kim, Kiyean Nam. Evaluation of the potential combination regimens for q901, a clinical stage selective cdk7 inhibitor, as a DNA damage repair inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5977.