Acquired resistance to gefitinib: The contribution of mechanisms other than the T790M, MET, and HGF status

Abstract

Background

Some types of somatic mutation of the epidermal growth factor receptor (EGFR) gene in non-small cell lung cancer (NSCLC) are associated with a significant clinical response to a tyrosine kinase inhibitor (TKI). However, most of the patients with this type of sensitive mutations in their tumor show acquired resistance during the TKI treatment.

Methods

The mutations in exons 19–21 of the EGFR gene were examined in both the pre-treatment and the post-treatment gefitinib resistant tumors in 10 patients with lung adenocarcinoma. Eight patients were recurrent cases after surgery, and two patients were non-surgical cases whose tumor specimens were obtained from the metastatic lymph node and endobronchially invading tumor.

Results

In 10 patients, 5 patients had a deletion in exon 19 and another 5 did L858R mutation in exon 21 of EGFR in gefitinib pre-treatment tumors. The mutation status did not change in the gefitinib-resistant tumors. In 7 of 10 patients, the gefitinib-resistant tumors had a secondary T790M mutation, which was not detected in the gefitinib pre-treatment tumors. In one patient, only one of the 4 gefitinib-resistant tumors showed the T790M mutation. Neither other novel secondary mutations of EGFR nor the K-ras were observed in their gefitinib-resistant tumors. Neither MET gene amplification nor HGF were observed in their gefitinib-resistant tumors without T790M mutation.

Conclusions

The T790M mutation in the EGFR is relatively common in the patients with acquired resistance to gefitinib. However, mechanisms other than T790M, MET, and HGF status are involved in resistance to gefitinib.

Introduction

An ATP-competitive inhibitor of EGFR such as gefitinib or erlotinib, demonstrated to be effective specifically in the treatment of adenocarcinoma of the lung, especially in Asian female patients without a smoking history [1], [2], [3]. The activating EGFR mutations such as the exon 19 deletion and the exon 21 L858R were observed in approximately 40–50% of adenocarcinoma [4], [5], and the tumors with these mutations have shown a significant sensitivity to EGFR-TKI [6], [7], [8], [9], [10], [11], [12], [13], [14], [15].

Despite an initial response to the treatment of the EGFR-TKI in such patients, most of the patients eventually proceed to progression of the disease, usually 6–12 months after the TKI treatment. The discovery of T790M was reported to explain partially the cause of phenomenon of the gefitinib-resistance [16], [17], [18], [19], where T790M leads to steric hindrance and interferences with the EGFR-TKI binding in the ATP kinase binding pocket [16]. At present, there are a few published reports on the molecular analyses of EGFR for acquired resistant tumor [16], [17], [18], [19] and the effectiveness of the re-administration of gefitinib after a pause of several months in patients who experienced initially favorable results was reported [20]. The reasons for such a phenomenon are not completely understood, while the K-ras mutations have been reported to be associated with some cases of primary resistance to EGFR-TKI [21]. In addition, MET amplification and over-expression of HGF have also been reported as causes of acquired resistant of EGFR-TKI [22], [23]. In the present study, we assessed the molecular analyses for gefitinib-refractory tumors after sensitive response to the treatment in order to elucidate existence of mechanism on acquired resistance to gefitinib other than T790M, MET, and HGF status.