Selected Articles from This Issue

KRASG12D is a dominant oncogenic driver in PDAC, CRC, and NSCLC, yet selective KRASG12D inhibition elicits adaptive resistance. In KRASG12D cancer models, MRTX1133 showed variable efficacy and induced heterogeneous activation of multiple receptor tyrosine kinases, revealing redundant bypass signaling that limits RTK targeting. To overcome this, a heterobifunctional strategy was developed to simultaneously inhibit KRASG12D and HSP90, a chaperone stabilizing activated RTKs and oncogenic signaling proteins. These dual inhibitors broadly suppressed bypass signaling, reduced AKT and ERK activity, and induced apoptosis, with response tracking with phospho-AKT suppression, establishing network-level targeting via HSP90 as a rational approach to constrain KRASG12D-driven resistance.CD30 is a key therapeutic target in classical Hodgkin lymphoma and several T-cell lymphomas, but current CD30-directed ADCs are limited by toxicities such as neutropenia and neurotoxicity. Here, Gerlach and colleagues describe TUB-010, a next-generation homogeneous DAR2 CD30-MMAE ADC generated using the site-specific, chemo-enzymatic Tub-tag conjugation platform. By stably attaching the payload to a natural, hydrophilic peptide derived from alpha-tubulin at the antibody light chain C-termini, TUB-010 shows improved stability, reduced aggregation and nonspecific uptake, resulting in high efficacy and better tolerability compared with Adcetris in preclinical models.There remains a significant unmet clinical need in HR+/HER2− breast cancer, necessitating the development of novel treatment options. As LIV-1 is consistently expressed in HR+ breast cancer and up-regulated after the development of endocrine therapy resistance, it represents a promising ADC target. We developed SDP-LIV1, a novel LIV-1 targeting ADC comprising a humanized LIV-1 mAb conjugated to a potent topoisomerase I inhibitor, with an optimized average DAR of 6. It demonstrates effective binding, internalization, and cytotoxic payload release with a potent bystander effect. Showing robust efficacy in xenograft models and a favorable safety profile in non-human primates, SDP-LIV1 is a promising therapeutic candidate currently in Phase I evaluation.Histologic transformation of prostate adenocarcinoma to neuroendocrine prostate cancer (NEPC) is associated with aggressive disease with limited treatment options. Ku and colleagues demonstrate how MK-6070, which binds to delta-like ligand 3 (DLL3) on the cell surface of NEPC tumor cells and CD3 on T cells, results in T cell activation and robust anti-tumor activity in preclinical models of NEPC. Responses were also seen in heterogenous tumors, including surrounding DLL3-negative tumor cells, support a potential bystander effect. These data provide mechanistic support for the development of DLL3-targeted treatment strategies for NEPC.