Synchronous EGFR and KRAS mutations in non-small cell lung carcinoma

Abstract

The range of chemotherapeutic options for non-small cell lung carcinoma (NSCLC) has been improved in recent years with the introduction of monoclonal antibodies designed to block signalling by the epidermal growth factor receptor (EGFR). In NSCLC, response to these novel therapeutic agents has been found to correlate to specific activating mutations in the EGFR gene.1 RAS genes encode GTPases as part of the MAP-kinase pathway of intracellular signalling. In contrast to EGFR mutations, tumours containing mutant KRAS are resistant to tyrosine kinase inhibitors,2 and indeed the current literature suggests that the two mutations are mutually exclusive.2,3 The aim of this study was to analyse samples of NSCLC for mutations in both the EGFR and KRAS genes to determine whether testing for KRAS mutations would provide any additional information over testing for EGFR mutations alone. Genomic DNA was available for testing from a total of 62 tumours. Regions of interest were amplified by touchdown PCR and mutations detected with Mutation Surveyor software (Softgenetics). EGFR mutations were detected in 37 tumours, KRAS mutations were detected in 12, and four tumours had mutations in both the EGFR and KRAS genes. The mutant EGFR receptors found in NSCLC have been shown to selectively activate Akt/STAT pathways, which are involved in anti-apoptotic mechanisms.4 This pathway is also activated by KRAS.5 Our finding that NSCLC can harbour mutations in both EGFR and KRAS is clinically significant, as these tumours are unlikely to respond to tyrosine kinase inhibitors as the Akt/STAT pathways would continue to be driven by the mutant KRAS. In addition, acquirement of a KRAS mutation may be an unrecognised pathway of acquired resistance to tyrosine kinase inhibitors. Thus we propose that simultaneous testing for KRAS mutations should be considered when testing for EGFR mutation is requested.