BACKGROUND Addition of CDK4/6 inhibitors (CDK4/6i) to endocrine therapy significantly increased progression-free survival, leading to their approval and incorporation into the metastatic breast cancer treatment paradigm. With these inhibitors being routinely used for patients with advanced estrogen receptor-positive (ER+) breast cancer, resistance to these agents and its impact on subsequent therapy needs to be understood. Considering the central role of ER in driving the growth of ER+ breast cancers, and thus endocrine agents being a mainstay in the treatment paradigm, the effects of prior CDK4/6i exposure on ER signaling and the relevance of ER-targeted therapy are important to investigate. The objective of this study was to evaluate the anti-tumor activity of elacestrant, a novel oral selective estrogen receptor degrader (SERD), in preclinical models of CDK4/6i resistance. METHODS Elacestrant was evaluated as a single agent, and in combination with alpelisib or everolimus, in multiple in vitro models and patient-derived xenografts that represent acquired and "de novo" CDK4/6i resistance. RESULTS Elacestrant demonstrated growth inhibition in cells resistant to all three approved CDK4/6i (palbociclib, abemaciclib, ribociclib) in both ESR1 wild-type and mutant backgrounds. Furthermore, we demonstrated that elacestrant, as a single agent and in combination, inhibited growth of patient-derived xenografts that have been derived from a patient previously treated with a CDK4/6i or exhibit de novo resistance to CDK4/6i. While the resistant lines demonstrate distinct alterations in cell cycle modulators, this did not affect elacestrant's anti-tumor activity. In fact, we observe that elacestrant downregulates several key cell cycle players and halts cell cycle progression in vitro and in vivo. CONCLUSIONS We demonstrate that breast cancer tumor cells continue to rely on ER signaling to drive tumor growth despite exposure to CDK4/6i inhibitors. Importantly, elacestrant can inhibit this ER-dependent growth despite previously reported mechanisms of CDK4/6i resistance observed such as Rb loss, CDK6 overexpression, upregulated cyclinE1 and E2F1, among others. These data provide a scientific rationale for the evaluation of elacestrant in a post-CDK4/6i patient population. Additionally, elacestrant may also serve as an endocrine backbone for rational combinations to combat resistance.

中文翻译：

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Elacestrant（RAD1901）在多种对CDK4 / 6抑制剂有抵抗力的ER +乳腺癌模型中表现出抗肿瘤活性。

背景技术向内分泌治疗中添加CDK4 / 6抑制剂（CDK4 / 6i）可以显着提高无进展生存期，从而导致其被批准并纳入转移性乳腺癌治疗范例。由于这些抑制剂通常用于晚期雌激素受体阳性（ER +）乳腺癌的患者，因此需要了解对这些药物的耐药性及其对后续治疗的影响。考虑到ER在驱动ER +乳腺癌生长中的核心作用，因此内分泌药物是治疗范例的主体，因此先前CDK4 / 6i暴露对ER信号转导的影响以及ER靶向治疗的相关性对于研究至关重要。这项研究的目的是评估一种新型口服选择性雌激素受体降解剂（SERD）的Elastestant的抗肿瘤活性，在CDK4 / 6i耐药的临床前模型中。方法在多种体外模型和患者来源的异种移植物中，以单药形式，与alpelisib或依维莫司联用，评估了ERESTESTANT表现为获得性和“新生的” CDK4 / 6i耐药性。结果在ESR1野生型和突变体背景下，Elastestrant均显示出对所有三种已批准的CDK4 / 6i（palbociclib，abeciclib，ribociclib）有抗性的细胞的生长抑制。此外，我们证明，作为单一药物或组合使用的促乳剂，可抑制源自患者的异种移植物的生长，所述异种移植物源自先前用CDK4 / 6i治疗过的患者，或者对CDK4 / 6i表现出全新的耐药性。尽管抗性品系在细胞周期调节剂中表现出明显的变化，但这并不影响清净剂的抗肿瘤活性。实际上，我们观察到，在体外和体内，流平剂下调了几个关键的细胞周期参与者，并中止了细胞周期进程。结论我们证明尽管暴露于CDK4 / 6i抑制剂，乳腺癌肿瘤细胞仍继续依赖ER信号驱动肿瘤生长。重要的是，尽管先前报道了观察到的CDK4 / 6i抗性机制，例如Rb丢失，CDK6过表达，cyclinE1和E2F1上调，但是，缓释剂仍可以抑制这种ER依赖性生长。这些数据为评估CDK4 / 6i后患者群体中的净白蛋白提供了科学依据。另外，清净剂还可以充当内分泌主干，以进行合理的组合以抵抗耐药性。我们观察到，在体外和体内，乳胶释放剂下调了几个关键的细胞周期参与者并中止了细胞周期的进程。结论我们证明尽管暴露于CDK4 / 6i抑制剂，乳腺癌肿瘤细胞仍继续依赖ER信号驱动肿瘤生长。重要的是，尽管先前报道了观察到的CDK4 / 6i抗性机制，例如Rb丢失，CDK6过表达，cyclinE1和E2F1上调，但是，缓释剂仍可以抑制这种ER依赖性生长。这些数据为评估CDK4 / 6i后患者群体中的净白蛋白提供了科学依据。另外，清净剂还可以充当内分泌主干，以进行合理的组合以抵抗耐药性。我们观察到，在体外和体内，乳胶释放剂下调了几个关键的细胞周期参与者并中止了细胞周期的进程。结论我们证明，尽管暴露于CDK4 / 6i抑制剂，乳腺癌肿瘤细胞仍继续依赖ER信号驱动肿瘤生长。重要的是，尽管先前报道了观察到的CDK4 / 6i抗性机制，例如Rb丢失，CDK6过表达，cyclinE1和E2F1上调，但是，缓释剂仍可以抑制这种ER依赖性生长。这些数据为评估CDK4 / 6i后患者群体中的净白蛋白提供了科学依据。另外，清净剂还可以充当内分泌主干，以进行合理的组合以抵抗耐药性。结论我们证明尽管暴露于CDK4 / 6i抑制剂，乳腺癌肿瘤细胞仍继续依赖ER信号驱动肿瘤生长。重要的是，尽管先前报道了观察到的CDK4 / 6i抗性机制，例如Rb丢失，CDK6过表达，cyclinE1和E2F1上调，但是，缓释剂仍可以抑制这种ER依赖性生长。这些数据为评估CDK4 / 6i后患者群体中的净白蛋白提供了科学依据。另外，清净剂还可以充当内分泌主干，以进行合理的组合以抵抗耐药性。结论我们证明尽管暴露于CDK4 / 6i抑制剂，乳腺癌肿瘤细胞仍继续依赖ER信号驱动肿瘤生长。重要的是，尽管先前报道了观察到的CDK4 / 6i抗性机制，例如Rb丢失，CDK6过表达，cyclinE1和E2F1上调，但是，缓释剂仍可以抑制这种ER依赖性生长。这些数据为评估CDK4 / 6i后患者群体中的净白蛋白提供了科学依据。另外，清净剂还可以充当内分泌主干，以进行合理的组合以抵抗耐药性。这些数据为评估CDK4 / 6i后患者群体中的净白蛋白提供了科学依据。另外，清净剂还可以充当内分泌主干，以进行合理的组合以抵抗耐药性。这些数据为评估CDK4 / 6i后患者群体中的净白蛋白提供了科学依据。另外，清净剂还可以充当内分泌主干，以进行合理的组合以抵抗耐药性。