KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib

William Pao, Theresa Y Wang, Gregory J Riely, Vincent A Miller, Qiulu Pan, Marc Ladanyi, Maureen F Zakowski, Robert T Heelan, Mark G Kris, Harold E Varmus, William Pao, Theresa Y Wang, Gregory J Riely, Vincent A Miller, Qiulu Pan, Marc Ladanyi, Maureen F Zakowski, Robert T Heelan, Mark G Kris, Harold E Varmus

Abstract

Background: Somatic mutations in the gene for the epidermal growth factor receptor (EGFR) are found in adenocarcinomas of the lung and are associated with sensitivity to the kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva). Lung adenocarcinomas also harbor activating mutations in the downstream GTPase, KRAS, and mutations in EGFR and KRAS appear to be mutually exclusive.

Methods and findings: We sought to determine whether mutations in KRAS could be used to further enhance prediction of response to gefitinib or erlotinib. We screened 60 lung adenocarcinomas defined as sensitive or refractory to gefitinib or erlotinib for mutations in EGFR and KRAS. We show that mutations in KRAS are associated with a lack of sensitivity to either drug.

Conclusion: Our results suggest that treatment decisions regarding use of these kinase inhibitors might be improved by determining the mutational status of both EGFR and KRAS.

Conflict of interest statement

Competing Interests: VAM has received research funding from Genentech (co-developer of erlotinib). He has received honoraria from AstraZeneca (maker of gefitinib) for consultancy. MGK has received research funding from AstraZeneca and research funding and consulting fees from Genentech and has represented AstraZeneca before the US Food and Drug Administration. WP, VAM, MFZ, and HEV, represented by the Sloan-Kettering Institute for Cancer Research, filed on June 1, 2004, a provisional patent application entitled “Use of mutations in EGFR kinase as an indicator of therapeutic efficacy of erlotinib in the treatment of NSCLC,” serial number 60/576,275. HEV is Co-founder and Chair of the Board of Directors of the Public Library of Science.

Figures

Figure 1. Sequence Chromatograms Displaying the Types…
Figure 1. Sequence Chromatograms Displaying the Types of KRAS Mutations Found in This Study

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Source: PubMed

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