DLK1 paper is live in Cancer Cell
A proteogenomic surfaceome study identifies DLK1 as an immunotherapeutic target in neuroblastoma
Amber K. Hamilton, Alexander B. Radaoui, Matthew Tsang, Daniel Martinez, Karina L. Conkrite, Khushbu Patel, Simone Sidoli, Alberto Delaidelli, Apexa Modi, Jo Lynne Rokita, Maria V. Lane, Nicholas Hartnett, Raphael D. Lopez, Bo Zhang, Chuwei Zhong, Brian Ennis, Daniel P. Miller, Miguel A. Brown, Komal S. Rathi, Pichai Raman, Jennifer Pogoriler, Tricia Bhatti, Bruce Pawel, Tina Glisovic-Aplenc, Beverly Teicher, Stephen W.Erickson, Eric J. Earley, Kristopher R. Bosse, Poul H. Sorensen, Kateryna Krytska, Yael P. Mosse, Karin E. Havenith, Francesca Zammarch, Patrick H. van Berkel, Malcolm A. Smith, Benjamin A. Garcia, John M. Maris, and Sharon J. Diskin
https://doi.org/10.1016/j.ccell.2024.10.003
Cancer immunotherapies produce remarkable results in B cell malignancies; however, optimal cell surface targets for many solid cancers remain elusive. Here, we present an integrative proteomic, transcriptomic, and epigenomic analysis of tumor and normal tissues to identify biologically relevant cell surface immunotherapeutic targets for neuroblastoma, an often-fatal childhood cancer. Proteogenomic analyses reveal sixty high-confidence candidate immunotherapeutic targets, and we prioritize delta-like canonical notch ligand 1 (DLK1) for further study. High expression of DLK1 directly correlates with a super-enhancer. Immunofluorescence, flow cytometry, and immunohistochemistry show robust cell surface expression of DLK1. Short hairpin RNA mediated silencing of DLK1 in neuroblastoma cells results in increased cellular differentiation. ADCT-701, a DLK1-targeting antibody-drug conjugate (ADC), shows potent and specific cytotoxicity in DLK1-expressing neuroblastoma xenograft models. Since high DLK1 expression is found in several adult and pediatric cancers, our study demonstrates the utility of a proteogenomic approach and credentials DLK1 as an immunotherapeutic target.