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

摘要：我们在过去几年的工作表明，细胞周期调节通路是至关重要的 内分泌治疗反应的决定因素以及经常采用的靶向治疗 治疗内质网转移性乳腺癌。在这里，我们将重点关注RB-肿瘤抑制通路，因为 与ER乳腺治疗相关的多条通路下游控制增殖的中央结节 癌症(如内分泌治疗和CDK4/6抑制剂)。而Rb是有效的细胞抑制剂所必需的 对ER乳腺癌采用的一系列靶向治疗的反应，多个途径可促进 “细胞周期可塑性”，因此代表了产生治疗抵抗的独特手段。在这里，我们将 描述这种形式耐药的潜在过程，诱导持久细胞周期停滞的手段，以及 临床观察的靶向抵抗的方法(目标1)。我们的数据和最新发表的研究表明 Rb丢失发生在ER乳腺癌中，是逃避细胞抑制治疗的一种手段。关于RB的分析 ER乳腺癌中的基因座表明在ER乳腺癌中有很大一部分发生13q的一个拷贝丢失 癌症，这表明这样的肿瘤已经准备好失去RB。如何随后治疗正在发生的 RB的异质性或单一的RB缺乏是一个重大的挑战。使用药物筛选和 有机类方法我们已经定义了几种对Rb阴性特别有效的方案 并可作为靶向CDK4/6抑制剂进展的ER肿瘤的一般手段(目标2)。 这些目标加在一起将询问进一步利用RB肿瘤抑制因子来实现精确度的方法 探讨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.