Endothelin-1–Mediated Drug Resistance in EGFR-Mutant Non-Small Cell Lung Carcinoma

Abstract

◥Progression on therapy in non-small cell lung carcinoma (NSCLC) is often evaluated radiographically, however, imagebased 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, EDNRantagonists 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 recombinant EDN significantly reduced blood flow and subsequent gefitinib accumulation in xenografted EGFRmutant 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 tumorassociated vasculature. Correlatively, these results describe a simplistic endogenous yet previously unrealized resistance mechanism inherent to a subset of EGFR-mutant NSCLC to attenuate tyrosine kinase inhibitor delivery to the tumors by limiting drug-carrying blood flow and the drug concentration in tumors.Significance: EDNR antagonists can be repurposed to improve drug delivery in VEGFA-secreting tumors, which normally respond to TKI treatment by secreting EDN1, promoting vasoconstriction, and limiting blood and drug delivery.

Variances in the Expression of mRNAs and miRNAs Related to the Histaminergic System in Endometrioid Endometrial Cancer

“…This is why current studies concern the use of EDNR antagonists in the context of carcinogenesis. These studies were based on the hypothesis that the EDN1-EDNR axis activates the MAPK-ERK signal pathway, which is necessary for the survival of cells that have been altered by cancer [ 34 ]. In our study, the obtained results allow us to confirm the fact that in the studied biopsies, an overexpression of the EDN1 and EDNRA genes occurred in comparison with the control group, independent of the degree of the histopathological endometrioid endometrial cancer (G).…”

“…In the blood samples, similar results can be observed; however, the highest overexpression of EDN1 was seen in G1 samples (EDNRA, similar to biopsies, had the highest overexpression in G2 in comparison with the control). Studies have proven that the inhibition of the mutated Epidermal Growth Factor (EGF) promotes the release of endothelin-1 (EDN1), which strengthens as cells that make up the mass of the tumor lose the epithelial phenotype in exchange for a mesenchymal one (epithelial–mesenchymal transition), which is a key factor determining metastasis [ 34 ]. This is in agreement with our observations made in the present work, as well as in a previous study where the expression of genes connected with EMT in endometrioid endometrial cancer samples was evaluated [ 27 ], and it is evidence of the progression of endometrioid endometrial cancer as well as the cells acquiring metastasis potential.…”

ERN1 knockdown modifies the impact of glucose and glutamine deprivations on the expression of EDN1 and its receptors in glioma cells

“…Furthermore, the endothelin axis (EDN1 and EDN1 receptor A) is involved in cellular growth, differentiation, cell motility, invasiveness, and tumor progression as well as drug resistance in several cancers. Polymorphisms of these genes increase the risk of papillary thyroid cancer developing (Aydin et al 2019;Pulido et al 2020). Recently, it was observed an abnormal expression of endothelin receptor type B (EDNRB) in hepatocellular carcinoma and confirmed its potential clinical significance (Zhang et al 2019).…”

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“…In lung cancer, it also promotes cell growth and induces drug resistance (Shi et al, 2020). In addition, although CAV1, SMAD7, BMP2, EDN1, and CXCL12 were not significantly different in the prognostic analysis in our study, they also play important roles in the occurrence and development of lung cancer (Katsura et al, 2018;Yan et al, 2019;Huang et al, 2020;Pulido et al, 2020;Tong et al, 2020). In general, the functions of target genes further confirmed the potential roles of those lncRNAs.…”