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

开发 CDK12 抑制剂以克服 HER2 和 KRAS 驱动的乳腺癌和肺癌的治疗耐药性

• 批准号: 10533580
• 负责人: Derek Ronald Duckett
• 金额: $ 2.92万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-12 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10533580
• 关键词: Breast Cancer Treatment; Cancer Patient; Cells; Cyclin-Dependent Kinases; Development; Drug resistance; ERBB2 gene; Evaluation; Future; Genetic Transcription; Goals; KRAS2 gene; Malignant Neoplasms; Malignant neoplasm of lung; Mission; Molecular; Molecular Probes; New Agents; Non-Small-Cell Lung Carcinoma; Pathway interactions; Patient-Focused Outcomes; Pharmaceutical Preparations; Property; Research; Resistance; Role; Signal Transduction; Stress; Testing; Transcriptional Regulation; United States National Institutes of Health; Xenograft Model; acquired drug resistance; anti-cancer; anti-cancer therapeutic; base; chemotherapy; clinical development; combat; disability; improved; in vivo; ineffective therapies; inhibitor; innovation; insight; malignant breast neoplasm; neoplastic cell; novel; novel strategies; novel therapeutics; pre-clinical; prevent; resistance mechanism; response; safety assessment; small molecule; targeted agent; targeted treatment; therapy resistant; treatment response; triple-negative invasive breast carcinoma

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.

项目摘要 尽管靶向疗法的发展改善了整体癌症患者的生存，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 反应，迫切需要增加治疗耐用性。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（CDK12）和13（CDK13）的抑制剂是强的候选者 打击获得获得的耐药性。该提案的长期目标是开发高效的CDK12/13 抑制剂具有一组适合于作为安全评估候选者推进的特性集的抑制剂 TNBC和HER2+乳腺癌和KRAS抑制剂NSCLC的治疗耐药性。总体 本应用中的目的是确定因处理指导的CDK12/13重新布线而改变的目标和途径 并开发出使这种重新布线的新疗法 - 可剥削的脆弱性。中心假设是 该CDK12/13充当转录和转录后适应的驱动力，并且针对CDK12/13 将阻止药物引起的逃生并改善乳腺癌和肺癌的治疗反应。理由 项目假定：（i）多个恶性肿瘤劫持CDK12/13来引起转录和信号可塑性 作为适应性应力的机制，以及（ii）阐明基于复合作用的机制 将提供一个强大的科学框架，以促进这些新代理的未来临床开发 改善患者的结果。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特异性抑制剂的药物样性能； （2）定义和验证机制 CDK12/13抑制可防止或逆转TNBC和HER2+乳腺癌的治疗耐药性（3） 定义和验证CDK12/13抑制阻止或逆转KRASG12C抑制剂的机制 NSCLC的阻力。因此，使用一系列方法，我们将：a）优化键CDK12/13抑制剂 参数提供安全评估候选人； b）定义和验证转录和翻译 机制，SR-4835引起对化学疗法的敏感性，c）验证基于细胞的基于细胞 临床前异种移植模型中的观察。我们的多PI应用程序的研究方法是创新的， 随着我们的团队发展出异常选择性和新颖的小分子CDK12/13体内活性分子 可以（i）对适应治疗耐药性的CDK12/13作用的探针（i）审问（ii） 评估中断转录控制的评估将对持久的抗拒机制进行抵抗，更多 耐用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 持续开发新型CDK12/13抑制剂。我们提出了对分子基础的洞察力 CDK12和CDK13驱动信号的主效应子，以及优化的CDK12/13抑制剂 将为改善乳腺癌和肺癌的组合治疗提供新的机会。