Dataset Information

Nuclear Pore Glycoprotein 62 Genetic Variant rs9523 is Associated with Clinical Outcomes of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Lung Adenocarcinoma Patients.

ABSTRACT:

Introduction

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have represented the prototype of targeted therapy in NSCLC. Patients with EGFR-mutant lung adenocarcinoma extract an extraordinary clinical benefit from EGFR-TKIs. However, the extent and duration of these responses are heterogeneous, suggesting the existence of genetic modifiers affecting an individual's response to TKIs. We investigated whether genetic variants in miRNA binding sites are associated with the clinical outcome of EGFR-TKIs in lung adenocarcinoma patients.

Methods

One hundred SNPs at miRNA binding sites in cancer-related genes were selected for the analysis using the crosslinking, ligation and sequencing of hybrids (CLASH) and CancerGenes database. qRT-PCR and luciferase assays were conducted to evaluate the functional relevance of the SNPs.

Results

NUP62 rs9523A>G were significantly associated with worse response to EGFR-TKIs, overall survival (OS), and progression-free survival (PFS). The other three SNPs (DVL2 rs2074216G>A, ARF1 rs11541557G>T, and UHRF1 rs2261988C>A) were significantly associated with worse OS and PFS. The rs9523A>G was significantly associated with decreased NUP62 expression in tumor tissues. In addition, a significantly decreased luciferase activity was noted in NUP62 rs9523 G allele compared to A allele.

Conclusion

Genetic variants in miRNA binding sites, especially NUP62 rs9523A>G, may be useful in predicting the clinical outcomes of EGFR-mutant lung adenocarcinoma patients treated with EGFR-TKIs.

SUBMITTER: Park JE

PROVIDER: S-EPMC8493114 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Publications

Nuclear Pore Glycoprotein 62 Genetic Variant rs9523 is Associated with Clinical Outcomes of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Lung Adenocarcinoma Patients.

Park Ji Eun JE Hong Mi Jeong MJ Lee Shin Yup SY Lee Jang Hyuck JH Choi Jin Eun JE Kang Hyo-Gyoung HG Do Sook Kyung SK Jeong Ji Yun JY Shin Kyung Min KM Lee Won Kee WK Choi Sun Ha SH Lee Yong Hoon YH Seo Hye Won HW Yoo Seung Soo SS Lee Jaehee J Cha Seung Ick SI Kim Chang Ho CH Park Jae Yong JY

Pharmacogenomics and personalized medicine 20211001

<h4>Introduction</h4>Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have represented the prototype of targeted therapy in NSCLC. Patients with EGFR-mutant lung adenocarcinoma extract an extraordinary clinical benefit from EGFR-TKIs. However, the extent and duration of these responses are heterogeneous, suggesting the existence of genetic modifiers affecting an individual's response to TKIs. We investigated whether genetic variants in miRNA binding sites are associated ...[more]

PMID: 34629889

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Project description:ImportanceMetformin hydrochloride is emerging as a repurposed anticancer drug. Preclinical and retrospective studies have shown that it improves outcomes across a wide variety of neoplasms, including lung cancer. Particularly, evidence is accumulating regarding the synergistic association between metformin and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs).ObjectiveTo assess the progression-free survival (PFS) in patients with advanced lung adenocarcinoma who received treatment with EGFR-TKIs plus metformin compared with those who received EGFR-TKIs alone.Design, setting, and participantsOpen-label, randomized, phase 2 trial conducted at the Instituto Nacional de Cancerología (INCan), Mexico City, Mexico. Eligible patients were 18 years or older, had histologically confirmed stage IIIB-IV lung adenocarcinoma with an activating EGFR mutation.InterventionsPatients were randomly allocated to receive EGFR-TKIs (erlotinib hydrochloride, afatinib dimaleate, or gefitinib at standard dosage) plus metformin hydrochloride (500 mg twice a day) or EGFR-TKIs alone. Treatment was continued until occurrence of intolerable toxic effects or withdrawal of consent.Main outcomes and measuresThe primary outcome was PFS in the intent-to-treat population. Secondary outcomes included objective response rate, disease control rate, overall survival (OS), and safety.ResultsBetween March 31, 2016, and December 31, 2017, a total of 139 patients (mean [SD] age, 59.4 [12.0] years; 65.5% female) were randomly assigned to receive EGFR-TKIs (n = 70) or EGFR-TKIs plus metformin (n = 69). The median PFS was significantly longer in the EGFR-TKIs plus metformin group (13.1; 95% CI, 9.8-16.3 months) compared with the EGFR-TKIs group (9.9; 95% CI, 7.5-12.2 months) (hazard ratio, 0.60; 95% CI, 0.40-0.94; P = .03). The median OS was also significantly longer for patients receiving the combination therapy (31.7; 95% CI, 20.5-42.8 vs 17.5; 95% CI, 11.4-23.7 months; P = .02).Conclusions and relevanceTo our knowledge, this is the first study to prospectively show that the addition of metformin to standard EGFR-TKIs therapy in patients with advanced lung adenocarcinoma significantly improves PFS. These results justify the design of a phase 3, placebo-controlled study.Trial registrationClinicalTrials.gov identifier: NCT03071705.

Dataset Information

Nuclear Pore Glycoprotein 62 Genetic Variant rs9523 is Associated with Clinical Outcomes of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Lung Adenocarcinoma Patients.

Introduction

Methods

Results

Conclusion

Publications

Nuclear Pore Glycoprotein 62 Genetic Variant rs9523 is Associated with Clinical Outcomes of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Lung Adenocarcinoma Patients.

Similar Datasets

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