Higher expression of miR-133b is associated with better efficacy of erlotinib as the second or third line in non-small cell lung cancer patients.

Alessandra Bisagni,Francesca Zanelli,Luca Braglia,Sally Maramotti,Martina Bonacini,Maria Pagano,Andrea Mozzarelli,Stefania Croci,Massimiliano Paci,Elena Tagliavini,Jung Weon Lee

doi:10.1371/journal.pone.0196350

Alessandra Bisagni, Francesca Zanelli + Show 9 more

Open Access

https://doi.org/10.1371/journal.pone.0196350

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Abstract

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (gefitinib, erlotinib and afatinib) are indicated as first-line therapy in patients with non-small cell lung cancer (NSCLC) whose tumors harbor activating mutations in the EGFR gene. Erlotinib is also used in second and third-line therapy for patients whose tumors have wild type EGFR but to date there are no validated biomarkers useful to identify which patients may benefit from this treatment. The expression level of four miRNAs: miR-133b, -146a, -7 and -21 which target EGFR was investigated by real-time PCR in tumor specimens from NSCLC patients treated with erlotinib administered as the second or third line. We found that miR-133b expression level better discriminated responder from non-responder patients to erlotinib. Higher levels of miR-133b in NSCLCs were associated with longer progression-free survival time of patients. Functional analyses on miR-133b through transfection of a miR-133b mimic in A549 and H1299 NSCLC cell lines indicated that increasing miR-133b expression level led to a decreased cell growth and altered morphology but did not affect sensitivity to erlotinib. The detection of miR-133b expression levels in tumors help in the identification of NSCLC patients with a better prognosis and who are likely to benefit from second and third-line therapy with erlotinib.

Highlights

Patients received a median of two chemotherapy regimens before a second- or third-line treatment with erlotinib
Detecting miR-133b expression levels in tumors might help in the identification of Non-Small Cell Lung Cancer (NSCLC) patients that are likely to benefit from second and third-line therapy with erlotinib
Studies in preclinical models are needed to demonstrate the therapeutic potential of miR-133b mimic and additional studies on larger cohorts of patients are required to validate the predictive value of miR-133b concerning response to erlotinib

Summary

Methods

Material & methods Patients and sample collectionPatients with lung adenocarcinoma in an advanced stage who received Erlotinb as second- or third-line therapy from January 2009 to December 2014 were included in the study. Exclusion criteria included concomitant primary cancer in other sites, comorbidities that contraindicate erlotinib treatment and incomplete clinical data. Tumour histologic grade was assessed according with the World Health Organization criteria (2015) [1]. Tumours were staged according with the 7th edition of the TNM staging system of the American Joint Committee on Cancer [32]. Objective tumor response was determined using Response Evaluation Criteria in Solid Tumours (RECIST Version 1.1). The patients with disease stabilization on erlotinib for at least 6 months were considered responders. Overall survival time (OS) was measured from the date of diagnosis to the date of death from any cause. Progression free survival (PFS) was defined as the time from erlotinib treatment start to the first observation of objective disease relapse or progression or death due to any cause

Results

Discussion

Conclusion