e15098 Background: In the landscape of cancer treatment, chemotherapy is the common treatment option for TNBC. However, resistance and tumor relapse remain the major obstacles hindering the effectiveness of chemotherapeutic agents in cancer patients. Therefore, the development of new therapeutics, especially targeted approaches like antibody-based therapies, holds immense significance. This study aims to identify and test the role of secretory protein/s that may support the growth and progression of TNBC cells. Additionally, it seeks to determine if targeting these secretory proteins with antibodies can provide a novel therapeutic approach for TNBC patients. Our study identified secretory protein SCUBE3 as a critical factor that promotes survival and therapy resistance of TNBC cells. Importantly, using antibody-development platform, our study presents a novel therapeutic approach targeting SCUBE3 using anti-SCUBE3 monoclonal antibody, offering new hope for TNBC patients with limited treatment options. Methods: High-throughput loss of function genomic screen was performed on TNBC cells in the presence or absence of doxorubicin to screen the oncoprotein. Mouse models was used to study the effect of SCUBE3 in shaping tumor immune microenvironment. Hybridoma culture was used to generate anti-SCUBE3 monoclonal antibodies. Screening of antibody producing clone was done based on ELISA, colony formation assay. Therapeutic efficacy of antibodies was evaluated in tumor xenograft models. Results: SCUBE3 functions extracellularly by engaging cell-surface receptors EGFR, CALR, and TGFβRI/II thereby activating FOXR2 and c-Myc signaling to promote pro-growth signals in cancer cell. SCUBE3-FOXR2 axis creates an immunosuppressive tumor microenvironment by facilitating recruitment of the Myc-DNMT1 repressor complex to the transcription regulator IRF1, thereby inhibiting antigen presentation. Anti-SCUBE3 antibody engineered with LALAPG mutation in the heavy chain showed enhanced specificity and efficacy. The antibody has shown high therapeutic potential across various cancer types in preclinical models, including breast and ovarian cancer patient-derived xenografts without any cytotoxic effects to major organs. This discovery support clinical development of anti-SCUBE3 antibody therapy as a therapeutic adjuvant for cancers characterized by hyperactive SCUBE3-associated signaling pathways. Conclusions: This study will set the stage for a new paradigm of treating TNBCs by inhibiting SCUBE3 activity. Our study is first to identify SCUBE3 as a novel ligand of EGFR1 and CALR mut . Notably, our study shows that SCUBE3 promotes pro-tumorigenic signaling cascade while inhibiting anti-tumor immunity to promote TNBC growth and render them resistant to therapy. Importantly, we provide compelling evidence that antibody targeting SCUBE3 may serve as a potent therapeutic for treating cancer with overexpressed SCUBE3.
Singh et al. (Thu,) studied this question.