UCLA researchers reported a preclinical strategy to increase the potency of antibody-drug conjugate approaches against metastatic castration-resistant prostate cancer (mCRPC) by combining targeted therapy blocks with a pro-survival pathway inhibitor. In laboratory experiments and mouse models, the team found that pairing antibody-drug conjugate–based targeted treatments with a drug that blocks BCL-XL produced substantially more anti-tumor activity, suggesting a way to overcome resistance mechanisms that limit durable responses in advanced disease. In a separate breast cancer study led by Houston Methodist and published in Clinical Cancer Research, investigators identified a signaling pathway that may help explain resistance to trastuzumab deruxtecan in metastatic HER2-positive breast cancer. The work points to S100–RAGE signaling as a potential driver of intrinsic drug resistance, and proposes that pathway blockade could restore tumor sensitivity—an angle that could inform future combination development in the difficult-to-treat resistance setting.