Targeting CDK7 with SY-1365: Unveiling a Novel Therapeutic Approach for Aggressive Solid Tumors

CDK7 has become a significant target in cancer research due to its role in reducing the expression of oncogenes regulated by super-enhancers (SEs). SY-1365, a covalent CDK7 inhibitor, has been shown to selectively induce apoptosis in leukemia cells without affecting non-malignant cells and has demonstrated anti-tumor effects in vivo. This study broadens the application of SY-1365 to solid tumors, identifying its efficacy in breast, ovarian, colorectal, and lung cancer cell lines with a low EC50 value and a swift induction of apoptosis. Notably, triple negative breast cancer (TNBC) cell lines were particularly sensitive to SY-1365, leading to further in vivo studies that confirmed significant tumor growth inhibition in patient-derived xenograft (PDX) models of TNBC.

The study also compared SY-1365's impact on gene expression with other gene control agents, such as a pan-CDK inhibitor, a CDK9 inhibitor, and a BRD4 inhibitor. Microarray analysis revealed a distinct transcriptional response from SY-1365, with a unique downregulation of genes related to oncogenic transcription factors, cell cycle regulation, and DNA damage response. The reduction in transcripts associated with apoptosis and DNA repair suggests a potential synergistic effect when SY-1365 is combined with agents targeting these pathways.

Indeed, the research found that SY-1365 synergized with the PARP inhibitor niraparib and the Bcl-2 inhibitor venetoclax in TNBC and AML cell lines, respectively. The findings underscore the sensitivity of TNBC, ovarian, and small cell lung cancer cell lines to SY-1365 and highlight the importance of apoptotic and DNA damage pathways in its mechanism of action. The study supports the exploration of SY-1365 in combination with PARP and Bcl-2 inhibitors as a potential therapeutic strategy.

Citation: Hu S, Ke N, Ren Y, Miljovska S, Rajagopal N, McKeown M, Orlando D, Sprott K, Choi YJ, Olson E, Fritz CC. SY-1365, a potent and selective CDK7 inhibitor, exhibits promising anti-tumor activity in multiple preclinical models of aggressive solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1151. doi:10.1158/1538-7445.AM2017-1151.