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Journal of Thoracic Oncology:
doi: 10.1097/JTO.0b013e3181cee47e
Brief Report

De Novo Resistance to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors in EGFR Mutation-Positive Patients with Non-small Cell Lung Cancer

Takeda, Masayuki MD, PhD*; Okamoto, Isamu MD, PhD*; Fujita, Yoshihiko PhD†; Arao, Tokuzo MD, PhD†; Ito, Hiroyuki MD, PhD‡; Fukuoka, Masahiro MD, PhD§; Nishio, Kazuto MD, PhD†; Nakagawa, Kazuhiko MD, PhD*

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Departments of *Medical Oncology, †Genome Biology, and ‡Pathology, Kinki University School of Medicine, Osaka-Sayama; and §Department of Medical Oncology, Kinki University School of Medicine, Sakai Hospital, Minami-ku, Sakai, Osaka, Japan.

Disclosure: The authors declare no conflict of interest.

Address for correspondence: Isamu Okamoto, Department of Medical Oncology, Kinki University School of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511, Japan. E-mail:

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Background: Somatic mutations in the epidermal growth factor receptor (EGFR) gene are a predictor of response to treatment with EGFR tyrosine kinase inhibitors (TKIs) in patients with non-small cell lung cancer (NSCLC). However, mechanisms of de novo resistance to these drugs in patients harboring EGFR mutations have remained unclear. We examined whether the mutational status of KRAS might be associated with primary resistance to EGFR-TKIs in EGFR mutation-positive patients with NSCLC.

Methods: Forty patients with NSCLC with EGFR mutations who were treated with gefitinib or erlotinib and had archival tissue specimens available were enrolled in the study. KRAS mutations were analyzed by direct sequencing.

Results: Three (7.5%) of the 40 patients had progressive disease, and two (67%) of these three individuals had both KRAS and EGFR mutations.

Conclusions: Our results suggest that KRAS mutation is a negative predictor of response to EGFR-TKIs in EGFR mutation-positive patients with NSCLC.

A total of 40 patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations were treated with gefitinib (n = 36) or erlotinib (n = 4) between September 2002 and January 2009, and three patients exhibited resistance to EGFR-tyrosine kinase inhibitor (TKIs). (i) Case 1 was a 63-year-old man who had never smoked and was diagnosed with lung adenocarcinoma of stage IV. Molecular screening identified a deletion mutation in exon 19 of EGFR, and he had received gefitinib as the second-line therapy. Although he tolerated gefitinib well, the primary lung lesion showed slow but steady growth, and he was removed from therapy because of his progressive disease (PD) at day 58 (Figure 1A). (ii) Case 2 was a 69-year-old man who had never smoked, had adenocarcinoma of stage IIIB, harbored a deletion in exon 19 of EGFR, and was treated with erlotinib as the third-line therapy. A chest computed tomography scan on day 28 revealed enlargement of the primary lung lesion, and the case was subsequently classified as PD (Figure 1B). (iii) Case 3 was a 52-year-old man who was a current smoker, had lung adenocarcinoma of stage IV with left adrenal metastasis, harbored a deletion in exon 19 of EGFR, and received erlotinib as the fourth-line therapy. Chest computed tomography on day 32 showed enlargement of the left adrenal metastasis, resulting in a classification of PD (Figure 1C). Thus, these clinical data demonstrated the existence of de novo resistance to EGFR-TKIs in EGFR mutation-positive patients. We examined the mutational status of KRAS in the three patients who showed PD as their best response. An amino acid substitution at codon 12 (G12D) of KRAS was identified in two of these three patients (Figure 1DF).

Figure 1
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Somatic mutations of the EGFR gene are associated with an increased response to EGFR-TKI in patients with NSCLC. Several prospective clinical trials of EGFR-TKI treatment for patients with NSCLC with EGFR mutations have subsequently revealed radiographic response rates of 55 to 91%. It remains of clinical concern, however, that a small proportion of patients with NSCLC with EGFR mutations show de novo resistance to EGFR-TKIs and that molecular markers to predict a lack of response to these drugs remain to be identified. We have now examined KRAS mutation status in EGFR mutation-positive patients with NSCLC treated with EGFR-TKIs and found a high incidence of concomitant KRAS mutation in individuals who did not respond to these drugs. Our results indicate that KRAS mutation may be clinically useful as a negative predictive marker of sensitivity to EGFR-TKIs in patients with NSCLC with EGFR mutations. Previous studies have also shown that KRAS mutations are associated with resistance to EGFR-TKIs in patients with NSCLC and that EGFR and KRAS mutations appear to be mutually exclusive in such patients,1–3 suggesting that KRAS mutations are predictors of unresponsiveness to EGFR-TKIs in patients with NSCLC with wild-type EGFR. The mutual exclusivity of EGFR and KRAS mutations combined with their prevalence patterns in lung adenocarcinoma, with KRAS mutations being preferentially found in smokers and EGFR mutations in nonsmokers, suggests that the mutations in these two genes might arise through different pathogenic pathways. Conversely, some studies have shown that KRAS mutations do sometimes coexist with EGFR mutations in patients with NSCLC.4,5 The extent of coexistence of EGFR and KRAS mutations in NSCLC thus remains unclear, in large part as a result of the low frequency of KRAS mutations, and the clinical relevance of KRAS mutations in EGFR mutation-positive patients has remained unknown. We have now shown that patients with NSCLC harboring EGFR mutations who exhibit de novo resistance to EGFR-TKIs have a high incidence of KRAS mutation, suggesting that the presence of KRAS mutations might provide a basis for the identification of EGFR mutation-positive patients who are unlikely to benefit from EGFR-TKI treatment. Our clinical findings are consistent with preclinical data showing that forced expression of mutant KRAS in PC-9 human NSCLC cells, which harbor an activating mutation of EGFR, resulted in a reduction in the sensitivity of these cells to gefitinib.6 Gefitinib shuts down both PI3K-AKT and RAS-RAF-MEK-ERK signaling pathways in PC-9 cells; however, expression of the KRAS mutant resulted in constitutive activation of these signaling pathways in a manner independent of EGFR activation, leading to continued cell growth and survival.

In July 2009, gefitinib received a license from the European Medicines Agency for all lines of therapy in patients with locally advanced or metastatic NSCLC positive for activating mutations of EGFR. More patients with EGFR mutation-positive tumors will thus now receive EGFR-TKIs. Our present results suggest that EGFR-TKIs should not be given routinely to patients harboring concomitant KRAS and EGFR mutations. In the event that such patients do receive treatment with EGFR-TKIs, they should be followed up after a short interval to obtain early evidence of possible tumor progression.

KRAS mutations cannot account for all cases of de novo resistance to EGFR-TKIs in EGFR mutation-positive patients with NSCLC. A recent study showed that loss of PTEN contributes to erlotinib resistance in an EGFR mutation-positive NSCLC cell line.7 Loss of PTEN resulted in partial uncoupling of the mutant EGFR from downstream signaling and further activated the receptor, leading to erlotinib resistance. Both homozygous deletion of PTEN and EGFR mutation were detected in one of 24 clinical specimens of NSCLC with EGFR mutations, although the efficacy of EGFR-TKIs was not evaluated in the corresponding patient.

In conclusion, our results suggest that KRAS mutation status should be assessed before initiation of EGFR-TKI treatment in EGFR mutation-positive patients with NSCLC, allowing enrichment of the population of such patients who are likely to prove responsive to the treatment.

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The authors thank Tadao Uesugi for technical assistance.

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1. Shigematsu H, Lin L, Takahashi T, et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst 2005;97:339–346.

2. Pao W, Wang TY, Riely GJ, et al. KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med 2005;2:e17.

3. Kosaka T, Yatabe Y, Endoh H, et al. Mutations of the epidermal growth factor receptor gene in lung cancer: biological and clinical implications. Cancer Res 2004;64:8919–8923.

4. Kalikaki A, Koutsopoulos A, Trypaki M, et al. Comparison of EGFR and K-RAS gene status between primary tumours and corresponding metastases in NSCLC. Br J Cancer 2008;99:923–929.

5. Han SW, Kim TY, Jeon YK, et al. Optimization of patient selection for gefitinib in non-small cell lung cancer by combined analysis of epidermal growth factor receptor mutation, K-ras mutation, and Akt phosphorylation. Clin Cancer Res 2006;12:2538–2544.

6. Uchida A, Hirano S, Kitao H, et al. Activation of downstream epidermal growth factor receptor (EGFR) signaling provides gefitinib-resistance in cells carrying EGFR mutation. Cancer Sci 2007;98:357–363.

7. Sos ML, Koker M, Weir BA, et al. PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer by activation of Akt and EGFR. Cancer Res 2009;69:3256–3261.

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Drug resistance; Epidermal growth factor receptor; KRAS; Non-small cell lung cancer; EGFR-TKI

© 2010International Association for the Study of Lung Cancer


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