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

项目摘要 尽管靶向治疗的发展提高了癌症患者的总体生存率，但适应性治疗仍然存在。 肿瘤细胞的反应可使这些治疗无效。阻止自适应的代理的开发 因此，迫切需要增加治疗的持久性。我们和其他人已经证明了 转录细胞周期蛋白依赖性激酶12（CDK 12）和13（CDK 13）的抑制剂是强有力的候选者， 来对抗获得性耐药性本提案的长期目标是开发一种高效的CDK 12/13 具有适合作为安全评估候选物推进以克服 在TNBC和HER 2+乳腺癌以及KRAS肿瘤抑制剂耐药NSCLC中，整体 本申请的目的是鉴定通过治疗导向的CDK 12/13重新连接而改变的靶点和途径 并开发新的疗法，使这种重新布线-一个可利用的弱点。核心假设是 CDK 12/13作为转录和转录后适应的驱动因子，靶向CDK 12/13 将阻断药物诱导的逃逸并改善乳腺癌和肺癌的治疗反应。这样做的理由 该项目假定：（i）多种恶性肿瘤劫持CDK 12/13，以激发转录和信号可塑性 作为一种适应性的抗逆机制，以及（ii）阐明复合作用的基础机制 将提供一个强有力的科学框架，促进这些新药物的未来临床开发， 改善患者预后。中心假设将通过追求三个具体目标进行测试：（1）优化 内部CDK 12/13特异性抑制剂的药物样性质;（2）定义和验证机制 其中CDK 12/13抑制预防或逆转TNBC和HER 2+乳腺癌中的治疗抗性（3） 定义并验证CDK 12/13抑制阻止或逆转KRASG 12 C抑制剂的机制 NSCLC中的耐药。因此，使用一系列方法，我们将：a）优化关键的CDK 12/13抑制剂 B）定义和验证转录和翻译参数， 机制，SR-4835由此引起对化疗的再敏感，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。我们的多PI应用程序的研究方法是创新的， 由于我们的团队已经开发出了非常具有选择性的新型小分子CDK 12/13体内活性分子， 探针，其将使得能够（i）在适应治疗抗性期间询问CDK 12/13的作用（ii） 评估，破坏转录控制将对抗抗性机制，提供持久的，更 持久的抗癌反应，甚至治愈;（iii）了解驱动癌症的关键信号节点。 耐药性拟议的研究非常重要，并提供了强有力的科学依据， 继续开发新型CDK 12/13抑制剂。我们提出了对分子基础的见解， CDK 12和CDK 13驱动的信号传导的主要效应物，以及优化的CDK 12/13抑制剂 将为改善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.