Developing CDK12 inhibitors to overcome therapy resistance in HER2+ and KRAS driven breast and lung cancers

项目概要 尽管靶向治疗的发展提高了癌症患者的总体生存率，但适应性 肿瘤细胞的反应会使这些治疗无效。阻止自适应代理的开发 反应，从而提高治疗的持久性是迫切需要的。我们和其他人已经证明 转录细胞周期蛋白依赖性激酶 12 (CDK12) 和 13 (CDK13) 的抑制剂是强有力的候选者 对抗获得性耐药性。该提案的长期目标是开发高效的CDK12/13 具有一系列特性的抑制剂，适合作为安全评估候选者来克服 TNBC 和 HER2 乳腺癌以及 KRAS 抑制剂耐药 NSCLC 的治疗耐药性。整体 本申请的目的是确定治疗导向的 CDK12/13 重连改变的靶点和途径 并开发新的疗法，使这种重新布线成为可利用的漏洞。中心假设是 CDK12/13 充当转录和转录后适应的驱动因素，并且靶向 CDK12/13 将阻止药物引起的逃逸并改善乳腺癌和肺癌的治疗反应。这样做的理由 该项目假设：(i) 多种恶性肿瘤劫持 CDK12/13 以激发转录和信号可塑性 作为一种适应性应激抵抗机制，以及（ii）阐明支撑复合作用的机制 将提供一个强大的科学框架，促进这些新药未来的临床开发 改善患者的治疗效果。将通过追求三个具体目标来检验中心假设：（1）优化 内部 CDK12/13 特异性抑制剂的类似药物特性； (2) 定义和验证机制 CDK12/13 抑制可预防或逆转 TNBC 和 HER2 乳腺癌的治疗耐药性 (3) 定义并验证 CDK12/13 抑制可预防或逆转 KRASG12C 抑制剂的机制 NSCLC 中的耐药性。因此，使用一系列方法，我们将： a) 优化关键的 CDK12/13 抑制剂 提供候选安全评估的参数； b) 定义并验证转录和翻译 SR-4835 引起对化疗重新敏感的机制，以及 c) 验证基于细胞的 临床前异种移植模型中的观察结果。我们的 Multi-PI 应用程序的研究方法是创新的， 因为我们的团队开发了具有特殊选择性的新型小分子CDK12/13体内活性分子 探针将能够 (i) 探究 CDK12/13 在适应治疗耐药过程中的作用 (ii) 评估破坏转录控制将对抗耐药机制，提供持久的、更多的 持久的抗癌反应甚至治愈； (iii) 了解驱动的关键信号节点 耐药性。拟议的研究非常重要，并为该研究提供了强有力的科学依据。 新型CDK12/13抑制剂的持续开发。我们提出对分子基础的洞察 CDK12 和 CDK13 驱动信号传导的主效应器以及优化的 CDK12/13 抑制剂 将为改进乳腺癌和肺癌的联合治疗提供新的机会。

Project Summary Although the development of targeted therapies has improved overall cancer patient survival, adaptive responses by tumor cells can render these treatments ineffective. The development of agents that block adaptive responses, thereby increasing treatment durability is desperately needed. We and others have demonstrated that inhibitors of the transcriptional cyclin-dependent kinases 12 (CDK12) and 13 (CDK13) are strong candidates to combat acquired drug resistance. The long-term goal of this proposal is to develop a highly effective CDK12/13 inhibitor with an aggregate set of properties suitable to advance as a safety assessment candidate to overcome therapy resistance in both TNBC and HER2+ breast cancers and KRAS inhibitor-resistant NSCLCs. The overall objective in this application is to identify targets and pathways altered by treatment-directed CDK12/13 rewiring and develop new therapeutics that render this rewiring - an exploitable vulnerability. The central hypothesis is that CDK12/13 acts as a driver of transcriptional and post-transcriptional adaptation and that targeting CDK12/13 will block drug-induced escape and improve treatment response in breast and lung cancer. The rationale for this project posits that: (i) multiple malignancies hijack CDK12/13 to provoke transcriptional and signaling plasticity as an adaptive stress resistance mechanism, and (ii) elucidation of mechanisms underpinning compound action will offer a strong scientific framework that will facilitate future clinical development of these new agents for improved patient outcome. The central hypothesis will be tested by pursuing three Specific Aims: (1) Optimize the drug-like properties of in-house CDK12/13 specific inhibitors; (2) Define and validate the mechanisms whereby CDK12/13 inhibition prevents or reverses treatment resistance in TNBC and HER2+ breast cancers (3) Define and validate the mechanisms whereby CDK12/13 inhibition prevents or reverses KRASG12C inhibitor resistance in NSCLC. Accordingly, using a battery of approaches, we will: a) optimize key CDK12/13 inhibitor parameters to deliver a safety assessment candidate; b) define and validate the transcriptional and translational mechanisms, whereby SR-4835 provokes resensitization to chemotherapy, and c) validate cell-based observations in pre-clinical xenograft models. The research approach of our Multi-PI application is innovative, as our team has developed exceptionally selective and novel small molecule CDK12/13 in vivo active molecular probes that will enable (i) interrogation of the roles of CDK12/13 during adaptation to treatment resistance (ii) evaluation that disrupting transcriptional control will counter-resistance mechanisms providing lasting, more durable anti-cancer responses or even cures; and (iii) understanding of the critical signaling nodes that drive drug resistance. The proposed research is highly significant and provides a strong scientific rationale for the continued development of novel CDK12/13 inhibitors. We submit that insight into the molecular underpinnings of the master effectors of CDK12 and CDK13-driven signaling, together with an optimized CDK12/13 inhibitor will offer new opportunities for improved combination treatments for breast and lung cancer.