Mechanisms of acquired resistance to EGFR-tyrosine kinase inhibitor in Korean patients with lung cancer

Abstract

BackgroundDespite an initial good response to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), resistance to treatment eventually develops. Although several resistance mechanisms have been discovered, little data exist regarding Asian patient populations.MethodsAmong patients at a tertiary referral hospital in Korea who initially responded well to gefitinib and later acquired resistance to treatment, we selected those with enough tissues obtained before EGFR-TKI treatment and after the onset of resistance to examine mutations by mass spectrometric genotyping technology (Asan-Panel), MET amplification by fluorescence in situ hybridization (FISH), and analysis of AXL status, epithelial-to-mesenchymal transition (EMT) and neuroendocrine markers by immunohistochemistry.ResultsTwenty-six patients were enrolled, all of whom were diagnosed with adenocarcinoma with EGFR mutations (19del: 16, L858R: 10) except one (squamous cell carcinoma with 19del). Secondary T790M mutation was detected in 11 subjects (42.3%) and four of these patients had other co-existing resistance mechanisms; increased AXL expression was observed in 5/26 patients (19.2%), MET gene amplification was noted in 3/26 (11.5%), and one patient acquired a mutation in the phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA) gene. None of the patients exhibited EMT; however, increased CD56 expression suggesting neuroendocrine differentiation was observed in two patients. Interestingly, conversion from L858R-mutant to wild-type EGFR occurred in one patient. Seven patients (26.9%) did not exhibit any known resistance mechanisms. Patients with a T790M mutation showed a more favorable prognosis.ConclusionThe mechanisms and frequency of acquired EGFR-TKI resistance in Koreans are comparable to those observed in Western populations; however, more data regarding the mechanisms that drive EGFR-TKI resistance are necessary.

Heterogeneity of resistance mutations detectable by next-generation sequencing in TKI-treated lung adenocarcinoma

“…As with other studies, our analysis found the most common post-TKI mutation to be p.T790M, occurring in 79% of patients compared to a reported range of approximately 40% to 60%[6, 26]. Our higher percentage is most likely due to a higher analytic sensitivity of the NGS assay.…”

“…Eight harbored a concomitant EGFR p.T790M mutation and the other case showed small cell carcinoma transformation. The finding of coexisting mechanisms of resistance has been described in studies examining post-TKI specimens [6, 26]. The significance of the PIK3CA mutation in these cases is uncertain.…”

The coexistence of MET over-expression and an EGFR T790M mutation is related to acquired resistance to EGFR tyrosine kinase inhibitors in advanced non-small cell lung cancer

“…The majority of studies have shown that the frequency of the T790M mutation in Asian populations is 40-50% [14, 15, 28]. We also observed that T790M mutation was the most common mechanism of EGFR-TKI resistance, representing 41.6% of all cases.…”

Therapeutic Strategies Utilized in the Setting of Acquired Resistance to EGFR Tyrosine Kinase Inhibitors

“…Combined inhibition of AXL and EGFR in these models restored therapeutic efficacy. More recently, increased AXL expression was observed in 5/26 patients (19%) of patients with AR to gefitinib (54). AXL inhibitors are in early clinical development (NCT00697632, ISRCTN00759419 and (55)).…”