RB tumor suppressor as a therapeutic target in ER-positive breast cancer

摘要：我们在过去几年的研究表明，细胞周期调控途径是至关重要的 对内分泌治疗以及经常采用的靶向治疗反应的决定因素 ER+转移性乳腺癌的治疗。在这里，我们将重点放在RB-肿瘤抑制途径， 控制与ER+乳腺癌治疗相关的多个途径下游增殖的中心节点 癌症（例如内分泌治疗和CDK 4/6抑制剂）。虽然RB是有效抑制细胞生长所必需的， 对ER+乳腺癌中采用的一系列靶向治疗的反应，多种途径可能有助于 “细胞周期可塑性”，并因此代表用于产生治疗抗性的不同手段。这里我们将 描述这种形式的抗性背后的过程，引起持久细胞周期停滞的手段，以及 临床上观察到的靶向耐药性的方法（目标1）。我们的数据和新发表的研究表明 RB丢失发生在ER+乳腺癌中，作为逃避细胞抑制疗法的手段。经常预算分析 ER+乳腺癌中的一个基因座表明13 q的一个拷贝的丢失发生在ER+乳腺癌的显著部分中。 这表明这种肿瘤是RB丢失的启动子。如何治疗肿瘤， RB的异质性或仅仅RB缺乏代表了重大挑战。使用药物筛选和 我们已经定义了几种对RB阴性的治疗方案， 并且可以代表靶向在CDK 4/6抑制剂上进展的ER+肿瘤的一般手段（Aim 2）。 这些目标将共同探讨进一步利用RB肿瘤抑制因子的方法， ER+乳腺癌的治疗方法。

ABSTRACT: Our work over the last several years, indicates that cell cycle regulatory pathways are critical determinants of the response to endocrine therapy as well as targeted therapies that are frequently employed in the treatment of ER+ metastatic breast cancer. Here we will focus on the RB-tumor suppressor pathway as a central node controlling proliferation downstream of multiple pathways of relevance to therapy of ER+ breast cancer (e.g. endocrine therapy and CDK4/6 inhibitors). While RB is required for the effective cytostatic response to a range of targeted therapies employed in ER+ breast cancer, multiple pathways can contribute to “cell cycle plasticity” and therefore represent distinct means for generating therapeutic resistance. Here we will delineate the processes underlying this form of resistance, means to elicit durable cell cycle arrest, and approaches to target resistance as observed clinically (Aim 1). Our data and newly published studies indicate that RB loss occurs in ER+ breast cancer as a means to escape from cytostatic therapies. Analysis of the RB locus in ER+ breast cancer indicates loss of one copy of 13q occurs in a significant fraction of ER+ breast cancers, suggesting that such tumors are primed for RB loss. How to subsequently treat tumors that are heterogeneous for RB or are solely RB deficient represents a significant challenge. Using drug screening and organoid approaches we have defined several regimens that are particularly effective against RB-negative tumors and could represent a general means to target ER+ tumors that progress on CDK4/6 inhibitors (Aim 2). Together these aims will interrogate means to further leverage the RB tumor suppressor for a precision approach to the treatment of ER+ breast cancer.