Abstract
A significant fraction of patients with lung adenocarcinomas harboring activating epidermal growth factor receptor (EGFR) mutations do not experience clinical benefits from EGFR tyrosine kinase inhibitor (TKI) therapy. Using next-generation sequencing, we screened 739 mutation hotspots in 46 cancer-related genes in EGFR L858R-mutant lung adenocarcinomas from 29 patients who received EGFR-TKI therapy; 13 had short (< 3 months) and 16 had long (> 1 year) progression-free survival (PFS). We discovered MLH1 V384D as a genetic variant enriched in the group of patients with short PFS. Next, we investigated this genetic variation in 158 lung adenocarcinomas with the EGFR L858R mutation and found 14 (8.9%) patients had MLH1 V384D; available blood or non-tumor tissues from patients were also tested positive for MLH1 V384D. Patients with MLH1 V384D had a significantly shorter median PFS than those without (5.1 vs. 10.6 months; P= 0.001). Multivariate analysis showed that MLH1 V384D polymorphism was an independent predictor for a reduced PFS time (hazard ratio, 3.5; 95% confidence interval, 1.7 to 7.2; P= 0.001). In conclusion, MLH1 V384D polymorphism is associated with primary resistance to EGFR-TKIs in patients with EGFR L858R-positive lung adenocarcinoma and may potentially be a novel biomarker to guide treatment decisions.
Highlights
Lung cancer has high incidence rates worldwide, and its 5-year survival is dismal as most cases are diagnosed at late stages
Derepression of FGFR2 expression has been implicated in the mechanism for rapidly acquired epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) resistance in non-small cell lung cancer (NSCLC) cells [12]
The DNA mismatch repair gene MLH1 has not been associated with EGFR-TKI resistance yet
Summary
Lung cancer has high incidence rates worldwide, and its 5-year survival is dismal as most cases are diagnosed at late stages. In 2004, somatic mutations were reported to exist in the tyrosine kinase domain of epidermal growth factor receptor (EGFR) in tumors of a subset of patients with non-small cell lung cancer (NSCLC) who responded dramatically to EGFR tyrosine kinase inhibitors (TKIs) [2,3]. This discovery has opened a new era of targeted therapy for NSCLC. Around 70% of patients with lung adenocarcinoma that has activating EGFR mutations (mostly a small in-frame deletion in exon 19 and a substitution mutation L858R) display objective clinical response to EGFR-TKI treatment [7,8,9,10,11]. The majority of resistant cases cannot be explained by these variations and the mechanistic basis for intrinsic EGFR-TKI resistance in patients supposed to be responsive is still largely unknown
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