Data from Reduced <i>NF1</i> Expression Confers Resistance to EGFR Inhibition in Lung Cancer

Abstract

<div>Abstract<p>Activating mutations in the EGF receptor (EGFR) are associated with clinical responsiveness to EGFR tyrosine kinase inhibitors (TKI), such as erlotinib and gefitinib. However, resistance eventually arises, often due to a second <i>EGFR</i> mutation, most commonly T790M. Through a genome-wide siRNA screen in a human lung cancer cell line and analyses of murine mutant EGFR-driven lung adenocarcinomas, we found that erlotinib resistance was associated with reduced expression of neurofibromin, the RAS GTPase-activating protein encoded by the <i>NF1</i> gene. Erlotinib failed to fully inhibit RAS–ERK signaling when neurofibromin levels were reduced. Treatment of neurofibromin-deficient lung cancers with a MAP–ERK kinase (MEK) inhibitor restored sensitivity to erlotinib. Low levels of <i>NF1</i> expression were associated with primary and acquired resistance of lung adenocarcinomas to EGFR TKIs in patients. These findings identify a subgroup of patients with <i>EGFR</i>-mutant lung adenocarcinoma who might benefit from combination therapy with EGFR and MEK inhibitors.</p><p><b>Significance:</b> The emergence of resistance to EGFR TKIs is a major clinical challenge in the treatment of lung adenocarcinomas driven by mutations in <i>EGFR</i>. This study suggests that, in a subset of patients, resistance is caused by reduced neurofibromin expression, and that in these cases there may be clinical benefit to combining EGFR TKIs with MEK inhibitors. <i>Cancer Discov; 4(5); 606–19. ©2014 AACR</i>.</p><p>See related commentary by Maertens and Cichowski, p. 519</p><p>This article is highlighted in the In This Issue feature, p. 495</p></div>