Endothelin-1-Mediated Drug Resistance in EGFR-Mutant Non-Small Cell Lung Carcinoma.
Inés PulidoStephen OllosiSalvador AparisiJeffrey H BeckerAlicia Aliena-ValeroMarta BenetMaría L RodríguezAdrián LópezEva Tamayo-TorresLourdes Chuliá-PerisJuan Carlos García-CañaverasMargaret SoucherayAnnika V DalheimJuan B SalomWei QiuSimon KajaJavier Alcácer Fernández-CoronadoSandra AlandesJavier AlcácerFátima Al-ShahrourJeffrey A BorgiaOscar Juan VidalMichael I NishimuraAgustin LahozJulián CarreteroTakeshi ShimamuraPublished in: Cancer research (2020)
Progression on therapy in non-small cell lung carcinoma (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 recombinant EDN 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 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.
Keyphrases
- blood flow
- small cell lung cancer
- epidermal growth factor receptor
- drug delivery
- signaling pathway
- tyrosine kinase
- induced apoptosis
- advanced non small cell lung cancer
- pi k akt
- cell cycle arrest
- clinical trial
- wild type
- papillary thyroid
- cell therapy
- brain metastases
- single cell
- oxidative stress
- endoplasmic reticulum stress
- cancer therapy
- emergency department
- bone marrow
- randomized controlled trial
- stem cells
- mesenchymal stem cells
- machine learning
- cell death
- drug release
- squamous cell
- young adults
- ultrasound guided
- transcription factor
- anti inflammatory
- replacement therapy
- combination therapy
- smoking cessation