Mayayo-Peralta Isabel, Faggion Beatrice, Hoekman Liesbeth, Morris Ben, Lieftink Cor, Goldsbrough Isabella, Buluwela Lakjaya, Siefert Joseph C, Post Harm, Altelaar Maarten, Beijersbergen Roderick, Ali Simak, Zwart Wilbert, Prekovic Stefan
Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
Proteomics Facility, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
Cancers (Basel). 2021 Dec 16;13(24):6314. doi: 10.3390/cancers13246314.
While endocrine therapy is highly effective for the treatment of oestrogen receptor-α (ERα)-positive breast cancer, a significant number of patients will eventually experience disease progression and develop treatment-resistant, metastatic cancer. The majority of resistant tumours remain dependent on ERα-action, with activating gene mutations occurring in 15-40% of advanced cancers. Therefore, there is an urgent need to discover novel effective therapies that can eradicate cancer cells with aberrant ERα and to understand the cellular response underlying their action. Here, we evaluate the response of MCF7-derived, CRISPR-Cas9-generated cell lines expressing mutant ERα (Y537S) to a large number of drugs. We report sensitivity to numerous clinically approved inhibitors, including CDK4/6 inhibitor ribociclib, which is a standard-of-care therapy in the treatment of metastatic ERα-positive breast cancer and currently under evaluation in the neoadjuvant setting. Ribociclib treatment induces senescence in both wildtype and mutant ERα breast cancer models and leads to a broad-range drug tolerance. Strikingly, viability of cells undergoing ribociclib-induced cellular senescence is maintained via engagement of EGFR signalling, which may be therapeutically exploited in both wildtype and mutant ERα-positive breast cancer. Our study highlights a wide-spread reduction in sensitivity to anti-cancer drugs accompanied with an acquired vulnerability to EGFR inhibitors following CDK4/6 inhibitor treatment.
虽然内分泌疗法对雌激素受体-α（ERα）阳性乳腺癌的治疗非常有效，但仍有相当数量的患者最终会出现疾病进展，并发展为耐药性转移性癌症。大多数耐药肿瘤仍然依赖于ERα的作用，在15%-40%的晚期癌症中会发生激活基因突变。因此，迫切需要发现能够根除具有异常ERα的癌细胞的新型有效疗法，并了解其作用背后的细胞反应。在此，我们评估了表达突变型ERα（Y537S）的MCF7衍生的CRISPR-Cas9生成的细胞系对大量药物的反应。我们报告了对多种临床批准的抑制剂的敏感性，包括CDK4/6抑制剂瑞博西尼，它是转移性ERα阳性乳腺癌治疗的标准护理疗法，目前正在新辅助治疗中进行评估。瑞博西尼治疗在野生型和突变型ERα乳腺癌模型中均诱导细胞衰老，并导致广泛的药物耐受性。引人注目的是，通过EGFR信号传导的参与，维持了经历瑞博西尼诱导的细胞衰老的细胞的活力，这在野生型和突变型ERα阳性乳腺癌中都可能具有治疗用途。我们的数据突出了对抗癌药物敏感性的广泛降低，以及在CDK4/6抑制剂治疗后对EGFR抑制剂获得性的易感性。
