Panitumumab-Based EGFR Blockade in SMARCB1-Deficient Renal Medullary Carcinoma: Preclinical Basis and Prospective Clinical Activity
Year: 2026
Type: article
Abstract: PURPOSE: SMARCB1-deficient renal medullary carcinoma (RMC) is an ultra-rare, lethal malignancy refractory to therapies approved for other renal cell carcinomas, and its rarity makes randomized trials logistically unfeasible. We investigated whether wild-type epidermal growth factor receptor (EGFR) is a therapeutically actionable dependency in RMC and translated this insight into a deployable clinical regimen. EXPERIMENTAL DESIGN: EGFR expression was assessed by CLIA-certified immunohistochemistry in RMC tumors and by integrated RNA- and chromatin immunoprecipitation-sequencing of primary tumors and adjacent kidney. Panitumumab was compared with erlotinib in patient- and cell line-derived xenografts, and its mechanism defined by immunoblotting, confocal colocalization, cell-cycle and apoptosis assays, and natural killer (NK) cell co-culture. Panitumumab-based therapy was then evaluated prospectively in 26 patients with RMC across ten centers on two continents. RESULTS: RMC showed uniformly high membranous EGFR (median H-score 300), with enhancer and promoter reprogramming at the EGFR locus and a ligand switch from EGF to epiregulin and amphiregulin. EGFR expression was uncoupled from SMARCB1 status in vitro. Panitumumab outperformed erlotinib in RMC xenografts, suppressed AKT and ERK1/2 signaling, and routed EGFR to LAMP1-positive lysosomes in vitro; its effect was predominantly cytostatic, with minimal NK cell-mediated cytotoxicity. Clinically, panitumumab-based therapy achieved a 53.9% objective response rate, including 15.4% complete responses, with median progression-free and overall survival of 5.8 and 9.5 months. CONCLUSIONS: Wild-type EGFR is a foundational dependency in RMC that is effectively targeted by panitumumab-based therapy. These findings, derived from a non-randomized registry, provide a biological and clinical rationale for further prospective validation.
Source: Clinical Cancer Research
Authors: Niki M. Zacharias, Eric S. Rupe, Xinyue Chen, Ritesh R. Kotecha, Damian T. Rieke, Bradley A. McGregor, Pedro Pesquera, Zhiyuan Yu, Abha Grover, Najat C. Daw, Emily Wang, Sze Wah Samuel Chan, Dorothea Douglas-Lindsay, Alice C. Fan, Eric M. Knoche, Christos E. Kyriakopoulos, Aly-Khan A. Lalani, Charlene M. Mantia, Amartej Merla, Martin H. Voss, Nicklas Pfanzelter, Sneha Ramakrishna, Neil M. Reaume, Tianyi Tang, Davis R. Ingram, Diana Shamsutdinova, Khalida M. Wani, Wei-Lien Wang, Alexander J. Lazar, Rahul A. Sheth, Priya Rao, Sandra L. Grimm, Cristian Coarfa, Rong He, Jing Qian, Fei Duan, Deepa Bisht, Pankaj K. Chauhan, Luigi Perelli, Giannicola Genovese, Liuqing Yang, Chunru Lin, Jose A. Karam, Ludovica La Posta, Eleonora Dondossola, Rafet Basar, Nadima Uprety, Katayoun Rezvani, Jianjun Gao, Linghua Wang, Luisa M. Solis Soto, Bora Lim, Nizar M. Tannir, Menuka Karki, Pavlos Msaouel
Institutions: The University of Texas MD Anderson Cancer Center, Memorial Sloan Kettering Cancer Center, Humboldt-Universität zu Berlin, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Charité - Universitätsmedizin Berlin, Dana-Farber Cancer Institute, Juravinski Cancer Centre, McMaster University, Nemours Children's Clinic, Stanford Medicine, Stanford University, Washington University in St. Louis, University of Wisconsin–Madison, City Of Hope National Medical Center, City of Hope, Endeavor Health, University of Ottawa, Ottawa Hospital, John Muir Health, Baylor College of Medicine, Dan L Duncan Comprehensive Cancer Center, The University of Texas Health Science Center at Houston, Rice University
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7203922654