Validating The Anti-Cancer Potency Of A Novel ROR1 Inhibitor Against Triple-Negative Breast Cancer

Abstract ID 126288 Poster Board 458 Breast cancer stands as the second most frequently diagnosed cancer among women in the United States. The particularly aggressive triple-negative breast cancer (TNBC) subtype constitutes 15-20% of new cases annually. Distinguished by the absence of estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER2), TNBC does not respond to typical hormone therapies like tamoxifen, fulvestrant, or letrozole. The standard TNBC treatment involves conventional chemotherapy and radiation, which impact both cancerous and normal cells. Given the absence of hormone receptors in TNBC, there is a need for exploring new anti-cancer compounds that specifically target TNBC while minimizing harm to non-cancerous tissues. Receptor orphan tyrosine kinase-like receptor 1 (ROR1) is an oncoprotein overexpressed in various malignancies, including lung, breast, prostate, and pancreatic cancers, but not in normal tissues. Inhibiting ROR1 signaling has demonstrated the ability to suppress cancer cell proliferation and induce apoptosis. Through in-silico docking, a novel compound, CPD4, was identified to dock to the pseudokinase domain of ROR1. Preliminary data showed that CD4 specifically targeted TNBC cells with minimal effects on non-malignant breast cells. Hence, it is posit that the anti-cancer mechanism of CD4 is by reducing the phosphorylation of AKT/GSK3β through ROR1 inhibition. In vitro results indicate that CPD4 inhibits TNBC cell viability and induces intrinsic apoptosis at a concentration of 2-10 μM, without affecting normal breast epithelial cells expressing minimal ROR1. CPD4 also hampers TNBC cell migration and invasion while sparing non-malignant cells at the IC50 dose. This study validates the potential of CPD4 as a therapeutic avenue for TNBC. The data presented serves as proof-of-concept justification for further evaluation in other cancers exhibiting upregulation of ROR1.