Abstract
Purpose: The past decade has witnessed the rapid development of personalized targeted therapies in lung cancer. It is still unclear whether epigenetic changes are involved in the response to tyrosine kinase inhibitor (TKI) treatment in epidermal growth factor receptor (EGFR)-mutated lung cancer.Experimental Design: Methyl-sensitive cut counting sequencing (MSCC) was applied to investigate the methylation changes in paired tissues before and after erlotinib treatment for 42 days with partial response (PR) from stage IIIa (N2) lung adenocarcinoma patients (N = 2) with EGFR 19 deletion. The Sequenom EpiTYPER assay was used to validate the changed methylated candidate genes. Up- or downregulation of the candidate gene was performed to elucidate the potential mechanism in the regulation of erlotinib treatment response.Results: Sixty aberrant methylated genes were screened using MSCC sequencing. Two aberrant methylated genes, CBFA2T3 and GABBR2, were clearly validated. A same differential methylated region (DMR) between exon 2 and exon 3 of GABBR2 gene was confirmed consistently in both patients. GABBR2 was significantly downregulated in EGFR 19 deletion cells, HCC4006 and HCC827, but remained conserved in EGFR wild-type A549 cells after erlotinib treatment. Upregulation of GABBR2 expression significantly rescued erlotinib-induced apoptosis in HCC827 cells. GABBR2 was significantly downregulated, along with the reduction of S6, p-p70 S6, and p-ERK1/2, demonstrating that GABBR2 may play an important role in EGFR signaling through the ERK1/2 pathway.Conclusions: We demonstrated that GABBR2 gene might be a novel potential epigenetic treatment target with induction erlotinib treatment for stage IIIa (N2) EGFR 19 deletion lung adenocarcinoma. Clin Cancer Res; 23(17); 5003-14. ©2017 AACR.
Highlights
Lung cancer has been the leading life-threatening cancer in the world [1]
GABBR2 was significantly downregulated, along with the reduction of S6, p-p70 S6, and p-ERK1/2, demonstrating that GABBR2 may play an important role in epidermal growth factor receptor (EGFR) signaling through the ERK1/2 pathway
We demonstrated that GABBR2 gene might be a novel potential epigenetic treatment target with induction erlotinib treatment for stage IIIa (N2) EGFR 19 deletion lung adenocarcinoma
Summary
Lung cancer has been the leading life-threatening cancer in the world [1]. With the development of molecular biology, targeted therapy has been more and more involved in anticancer treatment. In the clinical treatment of non–small cell lung cancer (NSCLC), targeted therapy against epidermal growth factor receptor (EGFR) has gradually matured and significantly contributed to the improvement of patient outcomes and quality of life [2]. The benefit of EGFR-TKI regimens for patients with stage IIIa NSCLC remains uncertain. The goal of the treatment in locally advanced NSCLC is to cure without long-term therapy related complications. With the successful integration of TKIs in the treatment of advanced NSCLC with mutated EGFR, it is reasonable to wonder whether we could extend this benefit to locally advanced NSCLC and improve long-term survival rates for these patients. There are some clinical trials (NCT01822496, NCT00600587) evaluating the value of induction erlotinib therapy before thoracotomy or radiotherapy in stage IIIa (N2) EGFR-mutated NSCLC. An important question is why the recurrence rates after complete surgical resection still remain as high as 70% [4]
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