目前，三阴性乳腺癌主要依靠化疗，而化疗耐药是三阴性乳腺癌的主要难题。既往研究已经发现，赖氨酰氧化酶抑制剂可以克服胰腺癌化疗耐药，并且可以抑制乳腺癌肺转移。不过，赖氨酰氧化酶抑制剂对于三阴性乳腺癌化疗耐药的作用尚不明确。
2020年5月15日，英国《自然》旗下《自然通讯》在线发表美国南卡罗来纳大学、土耳其比尔肯大学、安卡拉伊尔迪里姆贝亚兹特大学、安卡拉肿瘤教育研究医院、哈塞佩大学、加拿大麦吉尔大学的研究报告，探讨了赖氨酰氧化酶抑制剂对于三阴性乳腺癌化疗耐药的作用机制。
该研究通过核糖核酸（RNA）测序对体内肿瘤基因转录出的全部RNA特征进行分析，发现肿瘤微环境缺氧状态可以诱发赖氨酰氧化酶对肿瘤细胞外基质进行重塑，从而形成对化疗耐药的三阴性乳腺癌。
对赖氨酰氧化酶进行抑制，可以减少胶原蛋白交联和纤维连接蛋白装配，增加化疗药物渗透作用，并且减少整联蛋白ITGA5和纤维连接蛋白FN1的表达，从而抑制黏着斑激酶FAK和类固醇受体辅助激活因子Src的信号传导，诱发肿瘤细胞凋亡，并且对化疗恢复敏感。
同样，利用PF-562271或沙拉替尼对FAK和Src进行抑制，可以增强化疗敏感性。
上述作用已被三维培养细胞株、肿瘤类器官、化疗耐药异种移植肿瘤、同基因肿瘤和患者来源异种移植肿瘤模型证实。
重新表达受到缺氧抑制的小分子核糖核酸miR-142-3p对缺氧诱导因子HIF-1α、赖氨酰氧化酶、ITGA5进行抑制，可以进一步抑制HIF-1α→赖氨酰氧化酶→ITGA5和FN1的信号传导。
值得注意的是，如果赖氨酰氧化酶、ITGA5和FN1水平较高，或者miR-142-3p水平较低，那么三阴性乳腺癌化疗患者的生存时间显著较短。
因此，该研究结果表明，赖氨酰氧化酶抑制剂有望克服三阴性乳腺癌化疗耐药，故有必要进一步开展临床研究进行验证。
Nat Commun. 2020 May 15. [Epub ahead of print]
Targeting lysyl oxidase (LOX) overcomes chemotherapy resistance in triple negative breast cancer.
Ozge Saatci, Aysegul Kaymak, Umar Raza, Pelin G. Ersan, Ozge Akbulut, Carolyn E. Banister, Vitali Sikirzhytski, Unal Metin Tokat, Gamze Aykut, Suhail A. Ansari, Hayriye Tatli Dogan, Mehmet Dogan, Pouria Jandaghi, Aynur Isik, Fatma Gundogdu, Kemal Kosemehmetoglu, Omer Dizdar, Sercan Aksoy, Aytekin Akyol, Aysegul Uner, Phillip J. Buckhaults, Yasser Riazalhosseini, Ozgur Sahin.
University of South Carolina, Columbia, SC, USA; Bilkent University, Ankara, Turkey; Ankara Yildirim Beyazit University, Ankara, Turkey; Ankara Oncology Education and Research Hospital, Ankara, Turkey; McGill University, Montreal, QC, Canada; Hacettepe University, Ankara, Turkey.
Chemoresistance is a major obstacle in triple negative breast cancer (TNBC), the most aggressive breast cancer subtype. Here we identify hypoxia-induced ECM re-modeler, lysyl oxidase (LOX) as a key inducer of chemoresistance by developing chemoresistant TNBC tumors in vivo and characterizing their transcriptomes by RNA-sequencing. Inhibiting LOX reduces collagen cross-linking and fibronectin assembly, increases drug penetration, and downregulates ITGA5/FN1 expression, resulting in inhibition of FAK/Src signaling, induction of apoptosis and re-sensitization to chemotherapy. Similarly, inhibiting FAK/Src results in chemosensitization. These effects are observed in 3D-cultured cell lines, tumor organoids, chemoresistant xenografts, syngeneic tumors and PDX models. Re-expressing the hypoxia-repressed miR-142-3p, which targets HIF1A, LOX and ITGA5, causes further suppression of the HIF-1α/LOX/ITGA5/FN1 axis. Notably, higher LOX, ITGA5, or FN1, or lower miR-142-3p levels are associated with shorter survival in chemotherapy-treated TNBC patients. These results provide strong pre-clinical rationale for developing and testing LOX inhibitors to overcome chemoresistance in TNBC patients.
DOI: 10.1038/s41467-020-16199-4
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