KRAS Mutations and Primary Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib

Abstract

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

Molecular pathology of lung cancer: key to personalized medicine

“…5,6,14,63,64 In adenocarcinomas, the majority of mutations have been identified in exons 18-21 of the EGFR gene. 9,65,66 These mutations can be roughly classified into three major categories: in-frame deletions in exon 19, insertion mutations in exon 20, and missense mutations in exons 18-21 ( Figure 2).…”

“…[197][198][199] Mutations in KRAS, which are frequently found in adenocarcinomas with wildtype EGFR, are a mechanism of primary resistance to gefitinib and erlotinib. 63 PTEN is one of the key downstream components of the EGFR pathway and has a significant role in cell survival, proliferation, and growth. Knockdown of PTEN expression in cells results in drug resistance to gefitinib and erlotinib.…”

“…An activating mutation of KRAS is present in B25-35% of TKI non-responsive cases. 63 EGFR and KRAS mutations are rarely detected in the same tumor, suggesting that they may perform functionally equivalent roles in lung tumorigenesis. 205,206 KRAS mutation is a negative predictor of response to anti-EGFR monoclonal antibodies and is also an important mechanism of resistance to TKIs in lung adenocarcinomas.…”

Overview of molecular testing in non-small-cell lung cancer: mutational analysis, gene copy number, protein expression and other biomarkers of EGFR for the prediction of response to tyrosine kinase inhibitors

“…The need for repeat PCR to confirm mutations is less of a concern, as any mutations detected outside codons 12, 13 and 61 can be ignored. Pao et al (2005b) first suggested that patients with NSCLC whose tumors harbor mutations are resistant to EGFR TKI. To date, among 75 NSCLC patients harboring KRAS mutations who were treated with TKIs (Pao et al, 2005b;Hirsch et al, 2006;Massarelli et al, 2007;Miller et al, 2008;Zhu et al, 2008), only one patient has been reported to respond (Zhu et al, 2008).…”

Effectiveness of erlotinib treatment in advanced KRAS mutation-negative lung adenocarcinoma patients: Results of a multicenter observational cohort study (MOTIVATE)

“…Thus, patients with such characteristics are likely to respond better to erlotinib [15]. Moreover, the presence of KRAS mutations seems to be mutually exclusive with EGFR mutations, and is associated with the absence of response to EGFR-TKIs [16][17][18]. It has been confirmed that smokers with adenocarcinoma of the lung are more likely to have KRAS mutation positive tumors compared to non-smokers [6].…”