Improving the efficacy of B7-H3 targeting antibody-drug conjugates in TP53-deficient prostate cancer

Prostate cancer is the most diagnosed malignancy and the second leading cause of cancer-related death among men in the United States. Treatment options for advanced prostate cancers remain limited, and TP53 alterations occur in approximately 60% of prostate cancer cases and are associated with higher metastasis rates and worse overall outcomes. Effective therapies are urgently needed for advanced prostate cancers with TP53 defects. Immune checkpoint B7H3 is overexpressed in prostate cancer, and its overexpression correlates with increased risks of clinical recurrence and disease spread. DS-7300a is one of the most advanced B7H3-targeting antibody-drug conjugates (ADC) and has demonstrated clinical activity across multiple refractory malignancies. DS-7300a comprises a humanized anti-B7H3 monoclonal antibody warhead with topoisomerase I inhibitor, Dxd. In this study, we evaluated the efficacy of DS-7300a in prostate cancer that contains TP53 defects. Our results showed that the anti-tumor efficacy of DS-7300a is highly dependent on functional p53 in prostate cancer cells. Mechanistically, we found that DS-7300a and its payload Dxd induce DNA damage and activate the ATM/ATR/CHK signaling cascade, leading to p53 stabilization and transcriptional activation of pro-apoptotic and senescence-associated genes. In contrast, TP53 -deficient cells fail to sense DNA damage adequately and exhibit a high proliferation rate and low levels of apoptosis and senescence, leading to resistance to DS-7300a. Ferroptosis is an iron-dependent form of regulated cell death triggered by lipid peroxidation. Interestingly, we found that DS-7300a treatment induces lipid peroxidation as well as the expression of glutathione peroxidase 4 (GPX4), an antioxidant that mitigates lipid peroxidation, in TP53-deficient cancer cells. Taking advantage of our isogeneic xenograft models and a newly developed humanized B7H3 mouse model, we demonstrate that inducing ferroptosis by pharmacological inhibition of GPX4 enhanced the anti-tumor effects of DS-7300a in TP53 -deficient prostate cancer. Collectively, our studies indicate that p53 status dictates anti-tumor responses to DS-7300a in prostate cancer, and ferroptosis induction represents a promising therapeutic approach to overcome resistance to Dxd-based ADCs in malignancies harboring TP53 defects. Our studies will accelerate the development of effective therapies for prostate cancer patients with TP53 defects and provide a strong rationale for using TP53 status as a molecular biomarker to guide patient selection for clinical application of DS-7300a. This novel biomarker-driven combination strategy will also provide insights into the clinical trial design of Dxd-based ADCs and ferroptosis inducers in advanced prostate cancer and other malignancies.