Acquired Resistance of EGFR-Mutant Lung Adenocarcinomas to Afatinib plus Cetuximab Is Associated with Activation of mTORC1
Year: 2014
Type: article
Abstract: Patients with EGFR-mutant lung adenocarcinomas (LUADs) who initially respond to first-generation tyrosine kinase inhibitors (TKIs) develop resistance to these drugs. A combination of the irreversible TKI afatinib and the EGFR antibody cetuximab can be used to overcome resistance to first-generation TKIs; however, resistance to this drug combination eventually emerges. We identified activation of the mTORC1 signaling pathway as a mechanism of resistance to dual inhibition of EGFR in mouse models. The addition of rapamycin reversed resistance in vivo. Analysis of afatinib-plus-cetuximab-resistant biopsy specimens revealed the presence of genomic alterations in genes that modulate mTORC1 signaling, including NF2 and TSC1. These findings pinpoint enhanced mTORC1 activation as a mechanism of resistance to afatinib plus cetuximab and identify genomic mechanisms that lead to activation of this pathway, revealing a potential therapeutic strategy for treating patients with resistance to these drugs.
Source: Cell Reports
Authors: Valentina Pirazzoli, Caroline Nebhan, Xiaoling Song, Anna Wurtz, Zenta Walther, Guoping Cai, Zhongming Zhao, Peilin Jia, Elisa de Stanchina, Erik M. Shapiro, Molly Gale, Ruonan Yin, Leora Horn, David P. Carbone, Philip J. Stephens, Vincent Miller, Scott Gettinger, William Pao, Katerina Politi
Institutions: Yale Cancer Center, Yale University, Vanderbilt University, Vanderbilt University Medical Center, Memorial Sloan Kettering Cancer Center, Michigan State University, Vanderbilt-Ingram Cancer Center, The Ohio State University Wexner Medical Center, The Ohio State University, Foundation Medicine (United States)
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,620
Awards: G153582612, G1827975024, G2684890037, G3172769887, Overcoming acquired resistance to EGFR inhibitors in lung cancer, Medical Scientist Training Program, Mutant EGF Receptor-Dependent Lung Cancer in Human Cell Lines and Transgenic Mice, G435997112, The role of NF2 in Acquired Resistance to Targeted EGFR Inhibition in Lung Cancer, Single cell MRI of directed cell migration to stroke, Evolutionary Dynamics of Brain, Lung, and Hematopoietic Tumors, G725763919, Mechanisms of Mutant Epidermal Growth Factor Receptor Induced Lung Tumorigenesis, Cancer Center Support Grant
OpenAlex ID: W1986525211