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
Published in
Clinical cancer research : an official journal of the American Association for Cancer Research. Aug 21, 2026. Epub Aug 21, 2026.
Abstract
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.
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.
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.
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.
PMID:
42627757
Bibliographic data and abstract were imported from PubMed on 22 Aug 2026.
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