Panitumumab-Based EGFR Blockade in SMARCB1-Deficient Renal Medullary Carcinoma: Preclinical Basis and Prospective Clinical Activity

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.

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Journal
Clinical Cancer Research
Published
2026-08-21
DOI
https://doi.org/10.1158/1078-0432.ccr-26-0392
Primary Topic
Chromatin Remodeling and Cancer
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article
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article

Panitumumab-Based EGFR Blockade in SMARCB1-Deficient Renal Medullary Carcinoma: Preclinical Basis and Prospective Clinical Activity

Chunru Lin, Emily Wang, Damian Tobias Rieke, Katayoun Rezvani et al.
Clinical Cancer Research
Chromatin Remodeling and Cancer
article

Panitumumab-Based EGFR Blockade in SMARCB1-Deficient Renal Medullary Carcinoma: Preclinical Basis and Prospective Clinical Activity

Chunru Lin, Emily Wang, Damian Tobias Rieke, Katayoun Rezvani, Nadima Uprety, Sneha Ramakrishna, Amartej Merla, Rahul A. Sheth, M. Neil Reaume, Ritesh R. Kotecha, Davis R. Ingram, Menuka Karki, Rong He, Niki Marie Zacharias, Alice C. Fan, Charlene Mantia, Khalida Wani, Rafet Başar, Luigi Perelli, Aly‐Khan A. Lalani, Deepa Bisht, Giannicola Genovese, Alexander J. Lazar, Eleonora Dondossola, Linghua Wang, Liuqing Yang, Cristian Coarfa, Bora Lim, Sandra L. Grimm, Priya Rao, Nizar M. Tannir, Bradley A. McGregor, Christos E. Kyriakopoulos, Fei Duan, Jianjun Gao, Wei‐Lien Wang, Jing Qian, José A. Karam, Zhiyuan Yu, Abha Grover, Tianyi Tang, Luisa M. Solis Soto, Pavlos Msaouel, Sze Wah Samuel Chan, Najat C. Daw, Martin Henner Voss, Pedro I. Pesquera, Xinyue Chen, Pankaj Kumar Chauhan, Ludovica La Posta, Eric S Rupe, Diana Shamsutdinova, Eric Knoche, Dorothea Douglas-Lindsay, Nicklas Pfanzelter
article en

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.

Clinical Cancer Research
City Of Hope National Medical Center (US), Memorial Sloan Kettering Cancer Center (US), The University of Texas MD Anderson Cancer Center (US), University of Wisconsin–Madison (US), Baylor College of Medicine (US), Juravinski Cancer Centre (CA), Ottawa Hospital (CA), University of Washington Medical Center (US), Nemours Children’s Clinic (US), Endeavor Charter School (US), John Muir Medical Center (US), Dana-Farber Cancer Institute (US), Washington University Medical Center (US), Stanford Medicine (US), Nemours Children's Clinic (US), Charité - Universitätsmedizin Berlin (DE), Stanford University (US)
Good health and well-being
Openalex Percentile: Top 16%
Chromatin Remodeling and Cancer
DOISourceOpenAlex
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