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PTEN Loss Mediates Clinical Cross-Resistance to CDK4/6 and PI3Kα Inhibitors in Breast Cancer.
Cancer Discovery ( IF 29.7 ) Pub Date : 2020-01-01 , DOI: 10.1158/2159-8290.cd-18-0830
Carlotta Costa 1 , Ye Wang 1 , Amy Ly 2 , Yasuyuki Hosono 3 , Ellen Murchie 1 , Charlotte S Walmsley 1 , Tiffany Huynh 2 , Christopher Healy 1 , Rachel Peterson 1 , Shogo Yanase 3 , Charles T Jakubik 1 , Laura E Henderson 1 , Leah J Damon 1 , Daria Timonina 1 , Ioannis Sanidas 1 , Christopher J Pinto 1 , Mari Mino-Kenudson 2 , James R Stone 1 , Nicholas J Dyson 1 , Leif W Ellisen 1 , Aditya Bardia 1 , Hiromichi Ebi 3, 4, 5 , Cyril H Benes 1 , Jeffrey A Engelman 1 , Dejan Juric 1
Affiliation  

The combination of CDK4/6 inhibitors with antiestrogen therapies significantly improves clinical outcomes in ER-positive advanced breast cancer. To identify mechanisms of acquired resistance, we analyzed serial biopsies and rapid autopsies from patients treated with the combination of the CDK4/6 inhibitor ribociclib with letrozole. This study revealed that some resistant tumors acquired RB loss, whereas other tumors lost PTEN expression at the time of progression. In breast cancer cells, ablation of PTEN, through increased AKT activation, was sufficient to promote resistance to CDK4/6 inhibition in vitro and in vivo. Mechanistically, PTEN loss resulted in exclusion of p27 from the nucleus, leading to increased activation of both CDK4 and CDK2. Because PTEN loss also causes resistance to PI3Kα inhibitors, currently approved in the post-CDK4/6 setting, these findings provide critical insight into how this single genetic event may cause clinical cross-resistance to multiple targeted therapies in the same patient, with implications for optimal treatment-sequencing strategies. SIGNIFICANCE: Our analysis of serial biopsies uncovered RB and PTEN loss as mechanisms of acquired resistance to CDK4/6 inhibitors, utilized as first-line treatment for ER-positive advanced breast cancer. Importantly, these findings have near-term clinical relevance because PTEN loss also limits the efficacy of PI3Kα inhibitors currently approved in the post-CDK4/6 setting.This article is highlighted in the In This Issue feature, p. 1.

中文翻译:

PTEN 缺失介导了乳腺癌中对 CDK4/6 和 PI3Kα 抑制剂的临床交叉耐药性。

CDK4/6 抑制剂与抗雌激素疗法的组合显着改善了 ER 阳性晚期乳腺癌的临床结果。为了确定获得性耐药的机制,我们分析了接受 CDK4/6 抑制剂 ribociclib 与来曲唑联合治疗的患者的连续活检和快速尸检。该研究表明,一些耐药肿瘤获得了 RB 损失,而其他肿瘤在进展时失去了 PTEN 表达。在乳腺癌细胞中,通过增加 AKT 激活,消除 PTEN 足以在体外和体内促进对 CDK4/6 抑制的抵抗。从机制上讲,PTEN 丢失导致 p27 从细胞核中排除,导致 CDK4 和 CDK2 的激活增加。因为 PTEN 缺失也会导致对 PI3Kα 抑制剂的抗性,目前在 CDK4/6 后环境中获得批准,这些发现提供了关于这种单一遗传事件如何导致同一患者对多种靶向治疗的临床交叉耐药性的重要见解,并对最佳治疗测序策略产生影响。意义:我们对连续活检的分析发现 RB 和 PTEN 丢失是 CDK4/6 抑制剂获得性耐药的机制,可用作 ER 阳性晚期乳腺癌的一线治疗。重要的是,这些发现具有近期临床相关性,因为 PTEN 缺失也限制了目前在 CDK4/6 后环境中批准的 PI3Kα 抑制剂的功效。1. 这些发现提供了关于这种单一遗传事件如何导致同一患者对多种靶向治疗的临床交叉耐药性的重要见解,并对最佳治疗测序策略产生影响。意义:我们对连续活检的分析发现 RB 和 PTEN 丢失是 CDK4/6 抑制剂获得性耐药的机制,可用作 ER 阳性晚期乳腺癌的一线治疗。重要的是,这些发现具有近期临床相关性,因为 PTEN 缺失也限制了目前在 CDK4/6 后环境中批准的 PI3Kα 抑制剂的功效。1. 这些发现提供了关于这种单一遗传事件如何导致同一患者对多种靶向治疗的临床交叉耐药性的重要见解,并对最佳治疗测序策略产生影响。意义:我们对连续活检的分析发现 RB 和 PTEN 丢失是 CDK4/6 抑制剂获得性耐药的机制,可用作 ER 阳性晚期乳腺癌的一线治疗。重要的是,这些发现具有近期临床相关性,因为 PTEN 缺失也限制了目前在 CDK4/6 后环境中批准的 PI3Kα 抑制剂的功效。1. 我们对连续活检的分析发现 RB 和 PTEN 丢失是 CDK4/6 抑制剂获得性耐药的机制,可用作 ER 阳性晚期乳腺癌的一线治疗。重要的是,这些发现具有近期临床相关性,因为 PTEN 缺失也限制了目前在 CDK4/6 后环境中批准的 PI3Kα 抑制剂的功效。1. 我们对连续活检的分析发现 RB 和 PTEN 丢失是 CDK4/6 抑制剂获得性耐药的机制,可用作 ER 阳性晚期乳腺癌的一线治疗。重要的是,这些发现具有近期临床相关性,因为 PTEN 缺失也限制了目前在 CDK4/6 后环境中批准的 PI3Kα 抑制剂的功效。1.
更新日期:2020-04-21
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