Repurposing passenger amplifications as Trojan horses identifies MPZL1 as a potent target for solid cancers
Personalized cancer therapies focus mostly on targeting driver alterations, such as oncogenic point mutations or oncogenic driver events within large somatic copy number alterations. However, these alterations are often not actionable or only present in a small subset of patients. We hypothesized that passenger events, specifically in amplified regions, could be therapeutically exploited by providing actionable molecules on the cell surface, serving as Trojan horses for specific therapy delivery. Applying a multiomics in silico approach, we identified MPZL1 (Myelin protein zero-like 1), a glycosylated cell surface receptor located on chromosome 1q, as a promising candidate, which is amplified in up to 75% of cases in several solid cancers. Notably, immunohistochemistry of a wide range of human cancer tissues (n=2244 samples) as well as normal tissues revealed strong membranous MPZL1 expression in a majority of solid tumors (e.g. 48% of hepatocellular carcinomas or 89% of triple-negative breast cancers), whereas healthy tissues were mostly negative or just faintly positive for MPZL1. Next, we generated a highly specific monoclonal antibody directed to the extracellular domain of human MPZL1 protein and utilized this antibody to produce MPZL1 CAR-T cells. MPZL1 CAR-T cells showed high specificity as well as high sensitivity in targeting a multitude of human cancer cell lines (e.g. liver, breast, and lung cancer) with high MPZL1 expression in vitro. Finally, we demonstrate strong therapeutic efficiency of MPZL1 CAR-T cells not only in different human xenograft tumors in vivo but also in a unique autochthonous liver cancer mouse model. Our work provides a framework to target passenger events within large chromosomal amplifications, reveals MPZL1 as a new trojan horse entry point for therapies of 1q-amplified cancers, and as such opens a new avenue for innovative approaches in anti-cancer drug development.