Panitumumab-Based EGFR Blockade in SMARCB1-Deficient Renal Medullary Carcinoma: Preclinical Basis and Prospective Clinical Activity.
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Zacharias Niki M, Rupe Eric S, Chen Xinyue, Kotecha Ritesh R, Rieke Damian T, McGregor Bradley A, Pesquera Pedro, Yu Zhiyuan, Grover Abha, Daw Najat C, Wang Emily, Chan Sze Wah Samuel, Douglas-Lindsay Dorothea, Fan Alice C, Knoche Eric M, Kyriakopoulos Christos E, Lalani Aly-Khan A, Mantia Charlene M, Merla Amartej, Voss Martin H, Pfanzelter Nicklas, Ramakrishna Sneha, Reaume Neil M, Tang Tianyi, Ingram Davis R, Shamsutdinova Diana, Wani Khalida M, Wang Wei-Lien, Lazar Alexander J, Sheth Rahul A, Rao Priya, Grimm Sandra L, Coarfa Cristian, He Rong, Qian Jing, Duan Fei, Bisht Deepa, Chauhan Pankaj K, Perelli Luigi, Genovese Giannicola, Yang Liuqing, Lin Chunru, Karam Jose A, La Posta Ludovica, Dondossola Eleonora, Basar Rafet, Uprety Nadima, Rezvani Katayoun, Gao Jianjun, Wang Linghua, Solis Soto Luisa M, Lim Bora, Tannir Nizar M, Karki Menuka, Msaouel Pavlos
Аннотация
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.