Targeting lysyl oxidase (LOX) overcomes chemotherapy resistance in triple negative breast cancer
Özge Saatci, Aysegül Kaymak, Umar Raza, Pelin G. Ersan, Özge Akbulut, Carolyn E. Banister, Vitali Sikirzhytski, Ünal Metin Tokat, Gamze Aykut, Suhail A. Ansari, Hayriye Tatlı Doğan, Mehmet Doğan, Pouria Jandaghi, Aynur Işık, Fatma Gündoğdu, Kemal Kösemehmetoğlu, Ömer Dızdar, Sercan Aksoy, Aytekin Akyol, Ayşegül Üner, Phillip Buckhaults, Yasser Riazalhosseini, Özgür Şahin
Abstract
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.