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Tumor heterogeneity and resistance to EGFR-targeted therapy in advanced nonsmall cell lung cancer: challenges and perspectives

Authors Cheng X, Chen H

Received 21 April 2014

Accepted for publication 26 June 2014

Published 23 September 2014 Volume 2014:7 Pages 1689—1704

DOI https://doi.org/10.2147/OTT.S66502

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 5


Xinghua Cheng, Haiquan Chen

Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China

Abstract: Lung cancer, mostly nonsmall cell lung cancer, continues to be the leading cause of cancer-related death worldwide. With the development of tyrosine kinase inhibitors that selectively target lung cancer-related epidermal growth factor receptor mutations, management of advanced nonsmall cell lung cancer has been greatly transformed. Improvements in progression-free survival and life quality of the patients were observed in numerous clinical studies. However, overall survival is not prolonged because of later-acquired drug resistance. Recent studies reveal a heterogeneous subclonal architecture of lung cancer, so it is speculated that the tumor may rapidly adapt to environmental changes via a Darwinian selection mechanism. In this review, we aim to provide an overview of both spatial and temporal tumor heterogeneity as potential mechanisms underlying epidermal growth factor receptor tyrosine kinase inhibitor resistance in nonsmall cell lung cancer and summarize the possible origins of tumor heterogeneity covering theories of cancer stem cells and clonal evolution, as well as genomic instability and epigenetic aberrations in lung cancer. Moreover, investigational measures that overcome heterogeneity-associated drug resistance and new assays to improve tumor assessment are also discussed.

Keywords: NSCLC, EGFR, TKIs, drug resistance, tumor heterogeneity

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