Reduced NF1 expression confers resistance to EGFR inhibition in lung cancer.

Abstract:

: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 EGFR 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 NF1 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 NF1 expression were associated with primary and acquired resistance of lung adenocarcinomas to EGFR TKIs in patients. These findings identify a subgroup of patients with EGFR-mutant lung adenocarcinoma who might benefit from combination therapy with EGFR and MEK inhibitors.

journal_name

Cancer Discov

journal_title

Cancer discovery

authors

de Bruin EC,Cowell C,Warne PH,Jiang M,Saunders RE,Melnick MA,Gettinger S,Walther Z,Wurtz A,Heynen GJ,Heideman DA,Gómez-Román J,García-Castaño A,Gong Y,Ladanyi M,Varmus H,Bernards R,Smit EF,Politi K,Downward J

doi

10.1158/2159-8290.CD-13-0741

subject

Has Abstract

pub_date

2014-05-01 00:00:00

pages

606-19

issue

5

eissn

2159-8274

issn

2159-8290

pii

2159-8290.CD-13-0741

journal_volume

4

pub_type

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