Timbrell Simon, Aglan Hosam, Cramer Angela, Foden Phil, Weaver David, Pachter Jonathan, Kilgallon Aoife, Clarke Robert B, Farnie Gillian, Bundred Nigel J
Breast Biology Group, Manchester Breast Centre, Oglesby Cancer Research Building, University of Manchester, Manchester, UK.
Cancer Stem Cell Research, Oglesby Cancer Research Building, University of Manchester, Manchester, UK.
NPJ Breast Cancer. 2021 May 28;7(1):65. doi: 10.1038/s41523-021-00263-3.
Cancer stem-like cells (CSC) contribute to therapy resistance and recurrence. Focal adhesion kinase (FAK) has a role in CSC regulation. We determined the effect of FAK inhibition on breast CSC activity alone and in combination with adjuvant therapies. FAK inhibition reduced CSC activity and self-renewal across all molecular subtypes in primary human breast cancer samples. Combined FAK and paclitaxel reduced self-renewal in triple negative cell lines. An invasive breast cancer cohort confirmed high FAK expression correlated with increased risk of recurrence and reduced survival. Co-expression of FAK and CSC markers was associated with the poorest prognosis, identifying a high-risk patient population. Combined FAK and paclitaxel treatment reduced tumour size, Ki67, ex-vivo mammospheres and ALDH+ expression in two triple negative patient derived Xenograft (PDX) models. Combined treatment reduced tumour initiation in a limiting dilution re-implantation PDX model. Combined FAK inhibition with adjuvant therapy has the potential to improve breast cancer survival.
癌症干细胞（CSC）会导致治疗耐药性和复发。粘着斑激酶（FAK）在CSC调节中发挥作用。我们确定了FAK抑制单独以及与辅助治疗联合使用时对乳腺CSC活性的影响。FAK抑制降低了原发性人类乳腺癌样本中所有分子亚型的CSC活性和自我更新能力。FAK与紫杉醇联合使用可降低三阴性细胞系中的自我更新能力。一个浸润性乳腺癌队列证实，FAK高表达与复发风险增加和生存率降低相关。FAK与CSC标志物的共表达与最差的预后相关，确定了一个高危患者群体。在两个三阴性患者来源的异种移植（PDX）模型中，FAK与紫杉醇联合治疗可减小肿瘤大小、降低Ki67、减少体外乳腺球和ALDH+表达。联合治疗在有限稀释再植入PDX模型中降低了肿瘤起始。FAK抑制与辅助治疗联合使用有可能提高乳腺癌患者的生存率。
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