Small molecule targeting regulated cell death pathways in treating triple negative breast cancer

The absence of hormone and Her2 receptor expression in triple negative breast cancer (TNBC) precludes the use of targeted therapy available for other breast cancer subtypes, and cytotoxic chemotherapy such as paclitaxel and doxorubicin remains the mainstay of treatment for TNBC. However, patients with TNBC have higher relapse rates, with residual disease after chemotherapy and shorter overall survival, leaving space for further improvement beyond these cytotoxic chemotherapies. We have identified a new chemical entity, VMY- BC-1, that potently blocks growth in TNBC cell lines compared to other breast cancer subgroups or normal-like breast epithelial cells. Our molecule reduces invasion and induces apoptosis in TNBC cell lines. VMY-BC-1 is orally bioavailable and has promising pharmacological properties, and has demonstrated TNBC growth inhibition in vivo. Quantitative proteomics with tandem mass tag (TMT) and Ingenuity Pathway Analysis (IPA) identified significantly altered pathways upon treatment with VMY-BC-1 in the human TNBC cell line, MDA-MB-231. These include activation of the apoptosis, autophagy, and DNA damage pathways, and inhibition of the mTOR1, PI3K, and AKT pathways (Z score = 0.156, p value =1.97E-10). Thermal proteome profiling (TPP) analysis identified proteins interacting with VMY-BC-1 that relate to activated autophagy and DNA damage pathways, such as UNC-51 like kinase 1 (ULK1) and ataxia-telangiectasia mutated (ATM). Importantly, in line with our in vitro observations, in addition to a significantly lower expression of ULK1 on TNBC (T-test; p value = 2.127E-10), we observed that patients with tumors with high ULK1 expression have a larger relapse-free survival (n=3,951; HR=0.77 [0.69-0.86]; log rank; p=5.1E-06). Moreover, our small molecules activated autophagy mediated signaling pathways through ULK1 phosphorylation. These data suggest that autophagy and DNA damage pathways could be therapeutically targeted in TNBC. Citation Format: Venkata Mahidhar Yenugonda, Ariana Waters, Sivaramakrishna Yadavalli, Diego Marzese, Surojeet Senugupta, Elmar Nurmammadov, Yueqin Quan, Natsuko Nomura, Annamarie Allnutt, Santosh Kesari. Small molecule targeting regulated cell death pathways in treating triple negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-05-12.