Endothelin-1-mediated Drug Resistance in EGFR-mutant NSCLC. Journal Article

Authors: Pulido, I; Ollosi, S; Aparisi, S; Becker, JH; Aliena-Valero, A; Benet, M; Rodríguez, ML; López, A; Tamayo-Torres, E; Chuliá-Peris, L; García-Cañaveras, JC; Soucheray, M; Dalheim, AV; Salom, JB; Qiu, W; Kaja, S.; Alcácer Fernández-Coronado, J; Alandes, S; Alcácer, J; Al-Shahrour, F; Borgia, JA; Juan, O; Nishimura, MI; Lahoz, A; Carretero, J; Shimamura, T
Article Title: Endothelin-1-mediated Drug Resistance in EGFR-mutant NSCLC.
Abstract: Progression on therapy in NSCLC is often evaluated radiographically; however, image-based evaluation of said therapies may not distinguish disease progression due to intrinsic tumor drug resistance or inefficient tumor penetration of the drugs. Here we report that the inhibition of mutated EGFR promotes the secretion of a potent vasoconstrictor, endothelin-1 (EDN1), which continues to increase as the cells become resistant with a mesenchymal phenotype. As EDN1 and its receptor (EDNR) is linked to cancer progression, EDNR-antagonists have been evaluated in several clinical trials with disappointing results. These trials were based on a hypothesis that the EDN1-EDNR axis activates the MAPK-ERK signaling pathway that is vital to the cancer cell survival; the trials were not designed to evaluate the impact of tumor-derived EDN1 in modifying tumor microenvironment or contributing to drug resistance. Ectopic overexpression of EDN1 in cells with mutated EGFR resulted in poor drug delivery and retarded growth in vivo but not in vitro. Intratumoral injection of rEDN significantly reduced blood flow and subsequent gefitinib accumulation in xenografted EGFR mutant tumors. Furthermore, depletion of EDN1 or the use of endothelin receptor inhibitors bosentan and ambrisentan improved drug penetration into tumors and restored blood flow in tumor-associated vasculature. Correlatively, these results describe a simplistic endogenous yet previously unrealized resistance mechanism inherent to a subset of EGFR-mutant NSCLC to attenuate TKI delivery to the tumors by limiting drug-carrying blood flow and the drug concentration in tumors.
Journal Title: Cancer research
ISSN: 1538-7445; 0008-5472
Publisher: AACR  
Date Published: 2020