Sonia Jiménez-Vázquez, Anna Berthel, Christos Patsis, Mara Mitstorfer, Melanie Grimm, Luise Butthof, Lena Wendler-Link, Lio Böse, Hendrik Wiethoff, Ilse Hofmann, Kai Breuhahn, Thomas Longerich, Matthias M Gaida, Peter Schirmacher, Judith Feucht, Meggy Suarez-Carmona, Patrick Schmidt, Fee Klupp, Martin Schneider, Markus Wallwiener, Dirk Jaeger, Niels Halama, Marco Breinig, Darjus F Tschaharganeh
Most cancer therapies target genetic alterations driving tumor growth, but many drivers are undruggable or rare, limiting their therapeutic reach. Here, we demonstrate that amplified genes encoding cell surface proteins provide a rich, cancer-driver-agnostic source of targets. We identify MPZL1 (myelin protein zero-like 1), amplified in up to 75% of patients with certain solid tumor types, as abundantly expressed on the surface tumor cells across diverse cancer types while being largely absent from healthy tissues, offering a favorable therapeutic window. We develop a monoclonal antibody targeting MPZL1's extracellular domain and engineer chimeric antigen receptor (CAR)-T cells that selectively eliminate MPZL1-positive cancer cells in vitro. These CAR-T cells exhibit antitumor activity in human xenograft, autochthonous mouse, and patient-derived tissue explant preclinical models. This work establishes MPZL1 as a viable CAR-T cell target and provides a generalizable framework for exploiting amplified cell surface receptors as broadly applicable therapeutic targets.