Abstract 7198: A small molecule Notch1 inhibitor (ASR490) restores chemosensitivity in triple-negative breast cancer

Abstract

Abstract Metastatic triple-negative Breast cancer (mTNBC) is an aggressive and often a chemo resistant disease for which no effective druggable target has yet been identified. We and others reported that the aberrant expression of neurogenic locus Notch homolog protein 1 (Notch1) serves as a molecular signature for TNBC. Hence, we postulated that pharmacologically targeting Notch1 in conjunction with a standard chemotherapeutic agent (Doxorubicin: DXR) may completely eradicate TNBC growth and overcome systemic and debilitating toxicity. Hence, this study aims to elucidate the role of our recently discovered notch1 inhibitor ASR490 and its ability to chemosensitize TNBC without significant systemic toxicity. In our results, pretreatment of 1/10 th of the inhibitory concentration of ASR490 combined with 1/10 th or 1/20th of DXR significantly inhibited the growth of TNBC cells (MDA-MB-231 and BT549). Notably, DXR treatment induced Notch1 activation which led to chemoresistance in TNBC; however, co-treatment with the Notch1 inhibitor ASR490, led to the downregulation of Notch1 activation and eradication of the cell viability and clonogenicity of the TNBC cells. Further, molecular analysis suggested that pretreatment of 1/10th of ASR490 facilitates DXR-mediated sensitivity, by inhibiting the DNA repair pathway and upregulating (cleaved) caspase 3, (cleaved) caspase-9 and poly (ADP-Ribose) polymerase (PARP)-mediated apoptosis. Similarly, the combination effectively blocked the epithelial and mesenchymal transition (EMT) regulators and suppressed metastatic properties of MDA-MB231 and BT-549 cells. Moreover, combining ASR490(1/10th) and DXR (1/20th) significantly eradicated xenotransplanted TNBC tumors compared to ASR490 or DXR alone. In addition to being effective at inhibiting tumor growth, the significantly lower dose requirements of DXR and ASR490 in combination makes it a highly safe therapeutic modality. These findings suggest that aberrant activation of Notch1 is responsible for TNBC chemoresistance and concomitantly inhibiting Notch1 activation is an effective therapeutic strategy to restore chemosensitivity in TNBC. Citation Format: Neha Tyagi, Balaji Chandrasekaran, Ashish Tyagi, Balpreet Singh, Megha Chandran, Amandeep Singh, Arun Sharma, Chendil Damodaran. A small molecule Notch1 inhibitor (ASR490) restores chemosensitivity in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7198.