CDK7 inhibitors as a new strategy to overcome treatment resistance in ER+ metastatic breast cancer

项目摘要 大多数乳腺癌是雌激素受体阳性(ER+)，ER+乳腺癌是最主要的 导致乳腺癌死亡的原因。尽管对患者广泛采用辅助内分泌治疗 对于ER+乳腺癌，几乎所有ER+转移性疾病的患者最终都会对 内分泌治疗。人们提出了许多内分泌抵抗的机制，但大多数都是 主要基于临床前证据。最近，我们的小组和其他一些小组确定了 雌激素受体(ER)配体结合域(LBD)突变是卵巢癌最常见的基因组机制 ER阳性转移性乳腺癌患者存在内分泌抵抗。这些突变是相关的 ER+转移性乳腺癌患者总体生存率下降。CDK4/6抑制剂(CDK4/6I)对血管内皮细胞的作用 内分泌治疗已被证明可提高转移性ER+乳腺癌患者的无进展存活率 癌症，但尚未被证明能提高总体存活率。尽管取得了这一进展，但转移性癌症患者 疾病总是对这种联合疗法产生耐药性，用尽其他化疗方案，以及 最终死于他们的疾病。迫切需要开发新的治疗策略来克服 对内分泌治疗和CDK4/6I耐药。 我们的初步数据表明，选择性抑制CDK7可以克服对内分泌的抵抗 ER突变驱动的耐药性和CDK4/6I的耐药性。CDK7在转录和细胞中发挥关键作用 周期调节。SY1365是一种选择性的CDK7抑制剂，正处于癌症临床开发的早期阶段 治疗。本研究旨在综合研究SY1365作为单一制剂和在 氟维斯特联合治疗ER突变型内分泌耐药和CDK4/6I耐药ER+ 转移性乳腺癌。我们将研究CDK7抑制发挥抗肿瘤活性的机制 克服了ER突变导致的内分泌治疗耐药和CDK4/6I耐药。 由于CDK7使RNA聚合酶II磷酸化，同时也是一种CDK激活的激酶，我们将测试 SY1365对新生RNA和mRNA转录、CDK2磷酸化和细胞周期进程的影响 在ER+乳腺癌模型中。我们将研究对CDK7抑制和合成致死的抗性机制 SY1365存在时存在漏洞。最后，我们将检测SY1365在内分泌抵抗和 CDK4/6I耐药的PDX模型来源于ER+病患者的转移瘤。 这项研究的结果有可能导致一项临床试验，以测试疗效和靶向活性 用于治疗内分泌和CDK4/6I耐药ER+的新型药物选择性CDK7抑制剂 转移性乳腺癌。这些结果可能导致一种新的治疗策略，以改善患者的预后 相当数量的转移性ER+乳腺癌患者。

Project Abstract The majority of breast cancers are estrogen receptor positive (ER+) and ER+ breast cancer is the leading cause of breast cancer mortality. Despite the widespread adoption of adjuvant endocrine therapy for patients with ER+ breast cancer, almost all patients with ER+ metastatic disease will eventually develop resistance to endocrine treatments. A number of mechanisms of endocrine resistance were proposed but for the most these were predominantly based on preclinical evidence. Recently, our group and a number of other groups identified estrogen receptor (ER) ligand-binding domain (LBD) mutations as the most prevalent genomic mechanism of endocrine resistance identified in patients with ER+ metastatic breast cancer. These mutations are associated with decreased overall survival in ER+ metastatic breast cancer. The addition of CDK4/6 inhibitors (CDK4/6i) to endocrine treatment has been shown to improve progression free survival in patients with metastatic ER+ breast cancer, but have not been shown to improve overall survival. Despite this advance, patients with metastatic disease invariably develop resistance to this combined therapy, exhaust other chemotherapy options, and ultimately die of their disease. There is an urgent need to develop new therapeutic strategies to overcome resistance to endocrine treatment and CDK4/6i. Our preliminary data suggests that selective inhibition of CDK7 can overcome resistance to endocrine resistance driven by the ER mutations and resistance to CDK4/6i. CDK7 has key roles in transcriptional and cell cycle regulation. SY1365 is a selective CDK7 inhibitor that is in early stages of clinical development for cancer treatment. This study is designed to comprehensively study the activity of SY1365 as a single agent and in combination with fulvestrant for the treatment of ER mutant endocrine resistant and CDK4/6i resistant ER+ metastatic breast cancer. We will investigate the mechanisms by which CDK7 inhibition exerts anti-tumor activity and overcomes resistance to endocrine treatment driven by the ER mutations and resistance to CDK4/6i. Because CDK7 phosphorylates RNA polymerase II and also functions as a CDK-activating kinase, we will test the effects of SY1365 on nascent RNA and mRNA transcripts, CDK2 phosphorylation and cell cycle progression in ER+ breast cancer models. We will study mechanisms of resistance to CDK7 inhibition and synthetic lethal vulnerabilities in the presence of SY1365. Lastly, we will test the activity of SY1365 in endocrine resistant and CDK4/6i resistant PDX models derived from metastatic tumors from patients with ER+ disease. Results from this study have the potential to lead to a clinical trial testing the efficacy and on target activity of a new class of drugs, selective CDK7 inhibitors, for the treatment of endocrine and CDK4/6i resistant ER+ metastatic breast cancer. These results could lead to a new therapeutic strategy to improve outcomes in a substantial number of patients with metastatic ER+ breast cancer.