Abstract 578: Novel bi-thiazole LOX inhibitors to overcome chemotherapy resistance in triple negative breast cancer

Abstract

Abstract Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype accounting for around 15% of all breast cancer patients and is responsible for 30% of breast cancer-related deaths. Although chemotherapy is the mainstay therapy for TNBC, development of resistance significantly reduces patients’ survival. Therefore, there is an urgent need to identify novel and effective treatment strategies to overcome chemoresistance. Recently, we identified hypoxia-induced ECM re-modeler, lysyl oxidase (LOX), a member of LOX family, as a key mediator of chemoresistance in TNBC. In this study, combining a robust screening platform for drug-like molecules and cell-based/recombinant protein assays, we identified bi-thiazole derivatives as novel potent LOX inhibitors. Further structure activity relationship (SAR) analysis resulted in two lead compounds: 6403, a relatively LOX-specific inhibitor, and 6415, a more LOX/LOXL2 dual inhibitor. Both compounds reduced collagen crosslinking and led to chemosensitization in TNBC cell lines in 3D culture and in chemoresistant TNBC PDX organoids. Furthermore, re-analyses of scRNA-Seq data of TNBC patients treated with neo-adjuvant chemotherapy with known chemoresponse or resistance showed that LOX+ cells were enriched upon chemotherapy only in treatment-refractory patients. Importantly, we identified a significant correlation between LOX and the gene sets of Reactive Oxygen Species (ROS) and DNA repair in TNBC patients treated with chemotherapy. Supporting this, increased chemotherapy penetration upon LOX inhibition resulted in elevated ROS levels and DNA damage in cells, leading to inhibition of FAK/Akt survival signaling. The efficacy of 6403 was tested in a chemoresistant TNBC PDX model where combination of doxorubicin with LOX inhibitor overcame doxorubicin resistance with no significant change in body weights. State-of-the-art MALDI-MSI and MP-SHG experiments showed efficient reduction of collagen content and crosslinking, respectively in PDX tumors upon LOX inhibition. Overall, these results show that novel bi-thiazole LOX inhibitors block collagen crosslinking and potentiates chemotherapy-induced ROS-DNA damage axis to overcome chemoresistance in TNBC. Citation Format: Metin Cetin, Ozge Saatci, Abdol-Hossein Rezaeian, Ozge Akbulut, Nageswara Rao Chintada, Harrison Taylor, Breanna Pederson, Ioulia Chatzistamou, Hamed Shateri Najafabadi, Susan Lessner, Peggi Angel, Campbell McInnes, Ozgur Sahin. Novel bi-thiazole LOX inhibitors to overcome chemotherapy resistance in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 578.