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.

中文翻译：

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介质激酶抑制剂抑制三阴性乳腺癌生长，并延长 mTOR 和 AKT 抑制剂对肿瘤的抑制


三阴性乳腺癌 （TNBC） 主要通过化疗治疗，缺乏临床验证的治疗靶点。特别是，在许多乳腺癌中异常激活的 PI3K/AKT/mTOR 通路抑制剂由于适应性耐药性的发展而未能在 TNBC 中达到临床疗效，这主要是由 TNBC 的转录组可塑性驱动的。控制转录重编程的 CDK8/19 介体激酶的表达与乳腺癌患者（包括 TNBC）的无复发生存期和治疗失败相关。我们现在研究了 CDK8/19 抑制剂如何影响 TNBC 肿瘤的生长及其对 mTOR 和 AKT 抑制剂的反应。与大多数抗癌药物的作用相反，所有测试的人 TNBC 模型（包括患者来源的异种移植物）在体内对 CDK8/19 抑制剂有反应，即使它们在体外没有反应。此外，CDK8/19 抑制在小鼠 TNBC 模型中延长了已建立肺转移的宿主存活率，其中原发肿瘤没有显着影响。CDK8/19 抑制剂在体外与 mTORC1 抑制剂依维莫司和泛 AKT 抑制剂 capivasertib 协同作用，并在长期体内研究中强烈增强这些药物。对依维莫司有反应或适应的肿瘤的转录组学分析表明，体内药物适应与肿瘤和基质细胞的主要转录变化有关。依维莫司与 CDK8/19 抑制剂联合使用抵消了其中许多变化，并诱导了对影响肿瘤生长的多个基因表达的联合特异性影响。这些结果保证了 CDK8/19 介质激酶抑制剂作为 TNBC 治疗的新型药物的探索。