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 Discovjournal_title
Cancer discoveryauthors
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 Jdoi
10.1158/2159-8290.CD-13-0741subject
Has Abstractpub_date
2014-05-01 00:00:00pages
606-19issue
5eissn
2159-8274issn
2159-8290pii
2159-8290.CD-13-0741journal_volume
4pub_type
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