CDK4/6抑制剂联合内分泌治疗已成为雌激素受体阳性转移性乳腺癌患者的首选治疗方法。然而，对 CDK4/6 抑制剂的先天抗性的预测性生物标志物和机制仍然很大程度上未知。我们试图阐明对 CDK4/6 抑制剂耐药的患者的分子标志和治疗上可操作的特征。

共有 36 名接受帕博西尼和内分泌治疗的患者作为发现队列纳入本研究。对这些患者的循环肿瘤 DNA 进行了下一代测序，以评估与对帕博西尼的先天耐药性相关的体细胞改变。然后，候选生物标志物在另一个由 104 名患者和公开可用的数据集组成的独立队列中得到验证。在亲代 MCF-7 和 T47D 细胞以及它们的小干扰 RNA 转染和慢病毒感染的衍生物中验证了抗性。通过RNA测序、染色质免疫沉淀和荧光素酶测定检查了相关机制。患者来源的类器官和患者来源的异种移植物研究用于评估合理组合的抗肿瘤活性。

在发现队列中，S6K1 扩增（3/35, 9%）被确定为对 CDK4/6 抑制剂先天耐药的重要原因。在独立队列中，S6K1 在 15/104 (14%) 的患者中过度表达。在接在发现队列中，S6K1 扩增（3/35, 9%）被确定为对 CDK4/6 抑制剂先天耐药的重要原因。在独立队列中，S6K1 在 15/104 (14%) 的患者中过度表达。在接受帕博西尼治疗的患者中，S6K1 高表达患者的无进展生存期明显低于 S6K1 低表达患者（风险比 = 3.0，P = 0.0072）。公开数据的荟萃分析显示，S6K1 扩增的患者占乳腺癌的 12%。 S6K1 高表达的乳腺癌患者的无复发生存期显着降低（风险比 = 1.31，P < 0.0001）。在乳腺癌细胞中，由基因扩增引起的 S6K1 过表达足以促进对 palbociclib 的耐药性。从机制上讲，S6K1 过表达增加了 G1/S 转换相关蛋白的表达水平和 Rb 的磷酸化，主要通过激活 c-Myc 途径。值得注意的是，这种抗性可以通过添加mTOR 抑制剂来消除，该抑制剂在体外和体内阻断 S6K1 的上游。S6K1扩增是乳腺癌先天性对帕博西尼耐药的重要机制。对于 CDK4/6 和 S6K1 拮抗剂的组合，可以考虑 S6K1 扩增的乳腺癌。

Abstract

Background: CDK4/6 inhibitors combined with endocrine therapy has become the preferred treatment approach for patients with estrogen receptor-positive metastatic breast cancer. However, the predictive biomarkers and mechanisms of innate resistance to CDK4/6 inhibitors remain largely unknown. We sought to elucidate the molecular hallmarks and therapeutically actionable features of patients with resistance to CDK4/6 inhibitors.

Methods: A total of 36 patients received palbociclib and endocrine therapy were included in this study as the discovery cohort. Next-generation sequencing of circulating tumour DNA in these patients was performed to evaluate somatic alterations associated with innate resistance to palbociclib. Then the candidate biomarker was validated in another independent cohort of 104 patients and publicly available datasets. The resistance was verified in parental MCF-7 and T47D cells, as well as their derivatives with small interfering RNA transfection and lentivirus infection. The relevant mechanism was examined by RNA sequencing, chromatin immunoprecipitation and luciferase assay. Patient-derived organoid and patient-derived xenografts studies were utilized to evaluated the antitumor activity of rational combinations.

Results: In the discovery cohort, S6K1 amplification (3/35, 9%) was identified as an important reason for innate resistance to CDK4/6 inhibitors. In the independent cohort, S6K1 was overexpressed in 15/104 (14%) patients. In those who had received palbociclib treatment, patients with high-expressed S6K1 had significantly worse progression free survival than those with low S6K1 expression (hazard ratio = 3.0, P = 0.0072). Meta-analysis of public data revealed that patients with S6K1 amplification accounted for 12% of breast cancers. Breast cancer patients with high S6K1 expression had significantly worse relapse-free survival (hazard ratio = 1.31, P < 0.0001). In breast cancer cells, S6K1 overexpression, caused by gene amplification, was sufficient to promote resistance to palbociclib. Mechanistically, S6K1 overexpression increased the expression levels of G1/S transition-related proteins and the phosphorylation of Rb, mainly through the activation of c-Myc pathway. Notably, this resistance could be abrogated by the addition of mTOR inhibitor, which blocked the upstream of S6K1, in vitro and in vivo.

Conclusions: S6K1 amplification is an important mechanism of innate resistance to palbociclib in breast cancers. Breast cancers with S6K1 amplification could be considered for combinations of CDK4/6 and S6K1 antagonists.

原文链接

https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-022-01642-5

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