Repurposing passenger amplifications for specific therapeutic targeting of liver and other solid cancers

Current cancer therapies focus on targeting driver alterations responsible for tumorigenesis. However, these alterations are often not actionable or are only present in small a subset of patients. We hypothesized that passenger events in amplified regions could be therapeutically exploited by providing actionable molecules on the cell surface. Using publicly available multi-omics data, we identified the cell surface protein-coding gene MPZL1 (Myelin protein zero-like 1, in chromosome 1q), which is amplified in 75% of hepatocellular carcinomas (HCCs), accompanied high mRNA expression in tumors compared to normal livers. We further validated MPZL1 protein expression in a wide range of human cancer entities (n=2244) and normal tissues (n=90) by immunohistochemistry, and found that a high percentage of tumors present scores 2 or 3 (e.g. 48% of HCCs), whereas healthy tissues are mostly negative or faintly positive (scores 0 or 1). Next, we developed a monoclonal antibody directed to the extracellular domain of MPZL1, whose scFv was then used to generate a CAR (chimeric antigen receptor) construct targeting MPZL1. Corresponding CAR-T cells showed specific killing of several human cancer cell lines in vitro, along with enhanced cytotoxic cytokine production (TNFα, IFNγ, GZMB, IL-2) when encountering the specific antigen. Importantly, MPZL1-28ζ CAR-T cells induced complete eradication of murine autochthonous liver tumors with overexpression of human MPZL1 protein. In summary, our findings reveal MPZL1 as a new target for treatment of 1q-amplified cancers, opening an avenue for innovative drug development approaches by targeting passenger events within large chromosomal amplifications.

Publication History

Article published online:
20 January 2025