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存活率，但适应性 肿瘤细胞的反应可能使这些治疗无效。阻断自适应的代理的发展 因此，迫切需要提高治疗的耐久性。我们和其他人已经证明 转录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 以对抗获得性抗药性。这项提议的长期目标是开发一个高效的CDK12/13 具有一组适合作为要克服的安全评估候选者晋级的聚合属性的缓蚀剂 TNBC和HER2乳腺癌以及耐KRAS抑制剂的非小细胞肺癌的治疗耐药性。整体而言 本应用的目的是确定通过治疗指导的CDK12/13重连而改变的靶点和通路 并开发新的疗法，使这种重新布线成为一个可利用的漏洞。中心假设是 CDK12/13在转录和转录后适应中起驱动作用，靶向CDK12/13 将阻断药物诱导的逃逸，并提高乳腺癌和肺癌的治疗反应。这样做的理由是 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 作为一种适应性抗逆机制，以及(Ii)阐明支持复合作用的机制 将提供一个强大的科学框架，促进这些新药物的未来临床开发 改善了患者的预后。中心假设将通过追求三个具体目标来检验：(1)优化 内部CDK12/13特异性抑制剂的类药物特性；(2)确定和验证其作用机制 通过抑制CDK12/13预防或逆转TNBC和HER2乳腺癌的耐药性(3) 确定并验证CDK12/13抑制阻止或逆转KRASG12C抑制物的机制 非小细胞肺癌中的耐药性。因此，使用一系列方法，我们将：a)优化关键的CDK12/13抑制剂 提供安全评估候选方案的参数；b)定义和验证转录和翻译 机制，使SR-4835引发对化疗的再增敏，以及c)验证基于细胞的 临床前异种移植模型的观察。我们的多PI应用的研究方法是创新的， 由于我们的团队已经开发出具有特殊选择性和新颖的小分子CDK12/13体内活性分子 将能够(I)询问CDK12/13在适应抗药性过程中的作用的探针(Ii) 评估认为，扰乱转录控制将对抗耐药性机制，提供更持久、更 持久的抗癌反应或甚至治愈；以及(Iii)了解驱动癌症的关键信号节点 抗药性。这项拟议的研究具有非常重要的意义，并为 新的CDK12/13抑制剂的持续开发。我们提交了对分子基础的洞察 CDK12和CDK13驱动的信号转导的主效应子，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.