Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China.
Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
Mol Cancer. 2022 Aug 30;21(1):171. doi: 10.1186/s12943-022-01642-5.
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.
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.
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.
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.
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，CDK4/6 抑制剂先天耐药的预测生物标志物和机制在很大程度上仍不清楚。我们试图阐明对 CDK4/6 抑制剂耐药的患者的分子特征和治疗靶点。
本研究纳入了 36 名接受帕博西利和内分泌治疗的患者作为发现队列。对这些患者的循环肿瘤 DNA 进行下一代测序，以评估与帕博西利先天耐药相关的体细胞改变。然后，在另一个包含 104 名患者的独立队列和公开可用的数据集进行候选生物标志物验证。在亲本 MCF-7 和 T47D 细胞及其经小干扰 RNA 转染和慢病毒感染的衍生物中验证耐药性。通过 RNA 测序、染色质免疫沉淀和荧光素酶测定来研究相关机制。利用患者来源的类器官和患者来源的异种移植研究来评估合理组合的抗肿瘤活性。
在发现队列中，发现 S6K1 扩增（3/35，9%）是对 CDK4/6 抑制剂先天耐药的重要原因。在独立队列中，104 名患者中有 15 名（14%）S6K1 过表达。在接受帕博西利治疗的患者中，S6K1 高表达患者的无进展生存期明显短于 S6K1 低表达患者（风险比=3.0，P=0.0072）。对公开数据的荟萃分析显示，S6K1 扩增占乳腺癌的 12%。S6K1 表达水平高的乳腺癌患者无复发生存期明显较差（风险比=1.31，P<0.0001）。在乳腺癌细胞中，基因扩增导致的 S6K1 过表达足以促进对帕博西利的耐药性。机制上，S6K1 过表达通过激活 c-Myc 通路增加 G1/S 期转换相关蛋白的表达水平和 Rb 的磷酸化。值得注意的是，体外和体内添加可阻断 S6K1 上游的 mTOR 抑制剂可消除这种耐药性。
S6K1 扩增是乳腺癌对帕博西利先天耐药的重要机制。S6K1 扩增的乳腺癌可考虑联合 CDK4/6 和 S6K1 拮抗剂治疗。
