Abstract 1557: Defining modulators of response to samuraciclib, a CDK7 inhibitor for breast cancer

Abstract

Breast cancer (BC) is the most prevalent cancer in women worldwide. Despite initial sensitivity to endocrine therapies in hormone receptor positive BC, high mortality is driven by treatment-resistant disease. While several highly effective targeted treatments have been developed, resistance is common in the metastatic setting, highlighting the need for new therapies. Cyclin-dependent kinases (CDKs) have emerged as important targets for cancer treatment due to their integral role in driving the cell cycle. CDK4/6 inhibitors have advanced strongly in ER+ BC and are now becoming standard-of-care. However, resistance is a major problem. To address this, we have targeted CDK7, a master regulator of the cell cycle CDKs and transcription processes, both commonly dysregulated in cancer. CDK7 inhibition selectively inhibits cancer cell growth due to their reliance on aberrant gene expression and/or unregulated cell cycle progression. ICEC0942 (Samuraciclib), discovered in our lab at Imperial College London, has recently progressed to Phase 2 clinical trials. Considering the current clinical development of this and other CDK7 inhibitors (CDK7i), it is important to determine which patients will best respond to Samuraciclib. Towards identifying modulators of response to Samuraciclib, we performed a genome-wide CRISPR/Cas9-knockout screen in MCF7 cells. The mTOR/PI3K pathway was identified as important for response to CDK7i. Knockout of mTOR activators reduced sensitivity to Samuraciclib, while knockout of mTOR repressors increased sensitivity. Next, we studied the role of mutations in the catalytic subunit of PI3K (PIK3CA), which occur in nearly 30% of BC cases, in response to Samuraciclib. We utilized an isogenic panel of MCF10A cell lines, which were either wild-type for PIK3CA or had a heterozygous knock-in of either of the two most common mutations (E545K or H1047R). Cell growth was monitored following long-term (42-day) treatment with Samuraciclib. The drug was washed out (day 15) to determine the role of PIK3CA mutations in drug-induced growth arrest. We find that although Samuraciclib effectively inhibits growth of all cell lines, regardless of PIK3CA mutation status, the longevity of growth arrest post-washout is promoted by activating PIK3CA mutations. Finally, we assessed the role of mTOR and its downstream effectors in Samuraciclib response. Cell proliferation of MCF7 cells treated with Samuraciclib or in combination with mTOR/PI3K/AKT inhibitors was measured via flow cytometry. Samuraciclib treatment arrested cell proliferation; however, proliferation was reverted in combination with an mTOR/PI3K/AKT inhibitor. In conclusion, our findings highlight the importance of an active mTOR/PI3K pathway in promoting response to Samuraciclib. This may help guide patient treatments and development of effective combination therapies. Citation Format: Kaste Jurgaityte, Georgina Sava, Chun Fui Lai, Hailing Fan, Van Nguyen, Laki Buluwela, Simak Ali. Defining modulators of response to samuraciclib, a CDK7 inhibitor for breast cancer [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 1557.