Mediator kinase inhibitors suppress triple- negative breast cancer growth and extend tumor suppression by mTOR and AKT inhibitors

• 成果类型: Article
• 署名作者: Ding, Xiaokai; Liang, Jiaxin; Sharko, Amanda C.; Hilimire, Thomas A.; Li, Jing; Loskutov, Jurgen; Mack, Zachary T.; Ji, Hao; Schools, Gary P.; Cai, Chao; Pugacheva, Elena N.; Chen, Mengqian; Roninson, Igor B.; Broude, Eugenia V.
• 署名单位: University of South Carolina System; University of South Carolina Columbia; West Virginia University; University of South Carolina System; University of South Carolina Columbia
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-15098
• DOI: 10.1073/pnas.2414501121
• 发表日期: 2024-11-19
• 关键词: transcription

摘要

Triple- negative breast cancers (TNBC) are treated primarily by chemotherapy and lack clinically validated therapeutic targets. In particular, inhibitors of the PI3K/AKT/mTOR pathway, abnormally activated in many breast cancers, failed to achieve clinical efficacy in TNBC due to the development of adaptive drug resistance, which is largely driven by the transcriptomic plasticity of TNBC. Expression of CDK8/19 Mediator kinases that control transcriptional reprogramming correlates with relapse- free survival and treatment failure in breast cancer patients, including TNBC. We now investigated how CDK8/19 inhibitors affect the growth of TNBC tumors and their response to mTOR and AKT inhibitors. In contrast to the effects of most anticancer drugs, all the tested human TNBC models (including patient- derived xenografts) responded to CDK8/19 inhibitors in vivo even when they did not respond in vitro. Furthermore, CDK8/19 inhibition extended the host survival of established lung metastases in a murine TNBC model, where the primary tumors were not significantly affected. CDK8/19 inhibitors synergized with an mTORC1 inhibitor everolimus and a pan-AKT inhibitor capivasertib in vitro and strongly potentiated these drugs in long- term in vivo studies. Transcriptomic analysis of tumors that responded or became adapted to everolimus revealed that drug adaptation in vivo was associated with major transcriptional changes in both tumor and stromal cells. Combining everolimus with a CDK8/19 inhibitor counteracted many of these changes and induced combination- specific effects on the expression of multiple genes that affect tumor growth. These results warrant the exploration of CDK8/19 Mediator kinase inhibitors as a new type of drugs for TNBC therapy.