Combining cyclin-dependent kinase (CDK) inhibitors with endocrine therapy improves outcomes for patients with metastatic estrogen receptor-positive breast cancer but its value in earlier-stage patients is unclear. We examined evolutionary trajectories of early-stage breast cancer tumors, using single-cell RNA sequencing of serial biopsies from the FELINE clinical trial of endocrine therapy (letrozole) alone or combined with the CDK inhibitor ribociclib. Despite differences in subclonal diversity evolution across patients and treatments, common resistance phenotypes emerged. Resistant tumors treated with combination therapy showed accelerated loss of estrogen signaling with convergent upregulation of JNK signaling through growth factor receptors. In contrast, cancer cells maintaining estrogen signaling during mono- or combination therapy showed potentiation of CDK4/6 activation and ERK upregulation through ERBB4 signaling. These results indicate that combination therapy in early-stage estrogen receptor-positive breast cancer leads to emergence of resistance through a shift from estrogen to alternative growth signal-mediated proliferation.

将细胞周期蛋白依赖性激酶 (CDK) 抑制剂与内分泌治疗相结合可改善转移性雌激素受体阳性乳腺癌患者的预后，但其在早期患者中的价值尚不清楚。我们使用来自内分泌治疗（来曲唑）的 FELINE 临床试验单独或与 CDK 抑制剂 ribociclib 联合使用的连续活检的单细胞 RNA 测序，检查了早期乳腺癌肿瘤的进化轨迹。尽管不同患者和治疗的亚克隆多样性进化存在差异，但还是出现了常见的耐药表型。用联合疗法治疗的耐药肿瘤显示出雌激素信号的加速损失以及通过生长因子受体的 JNK 信号的收敛上调。相比之下，在单药或联合治疗期间维持雌激素信号的癌细胞显示通过 ERBB4 信号增强 CDK4/6 激活和 ERK 上调。这些结果表明，早期雌激素受体阳性乳腺癌的联合治疗通过从雌激素到替代生长信号介导的增殖的转变导致耐药性的出现。