Epidermal growth factor receptor tyrosine-kinase inhibitor treatment resistance in non-small cell lung cancer: biological basis and therapeutic strategies

Abstract

Lung cancer remains the leading cause of cancer-related death. Non-small cell lung cancer (NSCLC) represents 85 % of all lung cancer cases and it is classified into three major subtypes: adenocarcinoma, squamous cell carcinoma and large-cell carcinoma. In the past years, molecular-targeted therapies have been developed in order to improve response, survival and quality of life in patients with advanced NSCLC. Lung cancers harboring mutations in the epidermal growth factor receptor (EGFR) respond to EGFR tyrosine-kinase inhibitors (TKIs). However, virtually all patients with initial response relapse due to acquired resistance. Better understanding the biology of these tumors and mechanisms of EGFR TKIs resistance could shed some light on research of new therapeutic options in this setting. This review aims to emphasize on EGFR involved lung cancer pathway, primary and acquired mechanisms of TKIs resistance, and discuss agents currently used in clinical development in this emerging scenario.

Isoliquiritigenin Induces Apoptosis and Inhibits Xenograft Tumor Growth of Human Lung Cancer Cells by Targeting Both Wild Type and L858R/T790M Mutant EGFR

“…Although in current clinical settings, EGFR-TKIs are considered as first-line therapy (4), these drugs are less effective in NSCLC patients overexpressing wild type EGFR (7). The use of EGFR-TKIs also leads to the development of resistance, thereby limiting their longterm clinical success (8,9). Moreover, the genetic alterations in NSCLC are not only limited to EGFR but also mutation and/or amplification of several other genes, including Met, KRAS, and ErbB3, is associated with disease progression (3, 4, 6).…”

“…Although NSCLC harboring mutations in the EGFR respond well to EGFR-TKIs, virtually all patients with a good initial response will relapse due to acquired resistance. The acquired resistance to EGFR-TKIs has been shown to be associated with the secondary gatekeeper mutation, T790M (8,9). For instance, resistance to gefitinib appears within two years corresponding with mutation of EGFR (L858R/T790M) (10,11).…”

Advancing the Management of Non-small Cell Lung Cancer

“…44 Almost all patients with initial response to EGFR TKIs eventually relapse due to acquired resistance. 45 Around half of patients develop secondary Nintedanib A small molecule triple angiokinase inhibitor of VEGF1-3, PDGF-α and -β and FGFRI1-3…”

The antitumor effects of oncolytic adenovirus H101 against lung cancer

“…Immunodeficient homozygous SCID Beige male mice, 7-8 weeks of age, were obtained from Vital River Laboratories (Beijing, China). Back subcutaneous tumors were established by injection of 5x10 6 XWLC-05 cells in 100 µl of PBS. When tumor volume averaged ~100 mm 3 , 1x10 8 PFU of H101 in 100 µl was injected in tumor daily for 4 days.…”

“…Chemotherapy combinations for more advanced diseases have shown to convey no benefit on overall survival or quality of life beyond 4-6 cycles (3,4). NSCLC patients with epidermal growth factor receptor (EGFR) mutations initially respond to EGFR tyrosine kinase inhibitors, however, most patients experience a relapse within 1 year (5,6). Despite the development of novel molecular therapies, the prognosis of lung cancer is still poor and the 5-year survival remains <20% (7)(8)(9).…”