Azelnidipine may be a valuable drug for chemoprevention of ESCC with high MEK1/2 levels

Abstract

Esophageal squamous cell carcinoma (ESCC) is a high-incidence cancer worldwide. Standard fluoropyrimidine-plus-platinum-based chemotherapies for advanced ESCC are the main means and produce limited efficacy, with the median survival less than 1 year.1Sung H. Ferlay J. Siegel R.L. Laversanne M. Soerjomataram I. Jemal A. Bray F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA. Cancer J. Clin. 2021; 71: 209-249Crossref PubMed Scopus (20123) Google Scholar Therefore, it is urgent to find an effective therapeutic agent that can be used in patients with ESCC to prevent recurrence after primary treatment. Clinical available drugs are good resources for effective screening of therapeutic agents for ESCC.2Wei Y. Wu W. Jiang Y. Zhou H. Yu Y. Zhao L. Wu X. Lu X. Yuan Q. Wang Z. et al.Nuplazid suppresses esophageal squamous cell carcinoma growth in vitro and in vivo by targeting PAK4.Br. J. Cancer. 2021; 126: 1037-1046Crossref PubMed Scopus (5) Google Scholar,3Wu X. Wang Z. Jiang Y. Zhou H. Li A. Wei Y. Bao Z. Wang D. Zhao J. Chen X. et al.Tegaserod maleate inhibits esophageal squamous cell carcinoma proliferation by suppressing the peroxisome pathway.Front. Oncol. 2021; 11: 683241Crossref PubMed Scopus (8) Google Scholar Through screening FDA-approved drug libraries, Kangdong Liu et al. found that Azelnidipine, which is an anti-hypertensive drug, significantly inhibited the growth of ESCC.4Zhao L. Zhang Y. Li A. Lu X. Li M. Yuan Q. Yang N. Zhao X. Li X. Jiang Y. et al.Azelnidipine inhibits esophageal squamous cell carcinoma proliferation in vivo and in vitro by targeting MEK1/2.Mol. Ther. Oncol. 2022; 27: 61-72Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar It has been reported that Azelnidipine used in colorectal cancer immunotherapy showed significant inhibition on the growth of colorectal cancer by enhancing the quantity and activity of CD8+ T cells in the tumors.4Zhao L. Zhang Y. Li A. Lu X. Li M. Yuan Q. Yang N. Zhao X. Li X. Jiang Y. et al.Azelnidipine inhibits esophageal squamous cell carcinoma proliferation in vivo and in vitro by targeting MEK1/2.Mol. Ther. Oncol. 2022; 27: 61-72Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar However, the mechanism of how Azelnidipine inhibits the proliferation of ESCC is to be studied. This study provides a theoretical basis for clinical application of Azelnidipine on ESCC. Activation of the MEK-ERK signaling pathway occurs frequently in cancers.5Zhou X. Jiao L. Qian Y. Dong Q. Sun Y. Zheng W.V. Zhao W. Zhai W. Qiu L. Wu Y. et al.Repositioning azelnidipine as a dual inhibitor targeting CD47/SIRPα and TIGIT/PVR pathways for cancer immuno-therapy.Biomolecules. 2021; 11: 706Crossref PubMed Scopus (11) Google Scholar In the MEK-ERK pathway, MEK1/2 is a “gatekeeper” that transducts signals from multiple upstream regulators to ERK1/2, and the high activity of MEK1/2 modulates cell proliferation and drug resistance. In this study, the authors predicted that MEK1 and MEK2 may be the potential target of Azelnidipine by computational modeling and verified that Azelnidipine bound with MEK1. Meaningfully, in this study, Azelnidipine reduced the levels of p-ERK1/2 T202/Y204, CDK6, and cyclin D1 in ESCC cells, which arrested cells to G1 phase. Currently, trametinib, the second generation of MEK1/2 inhibitors, has been put into clinical application for several cancer types,6Burotto M. Chiou V.L. Lee J.M. Kohn E.C. The MAPK pathway across different malignancies: a new perspective.Cancer. 2014; 120: 3446-3456Crossref PubMed Scopus (582) Google Scholar However, trametinib has significant adverse reaction such as rash, diarrhea, peripheral edema, and fatigue. In this study, Azelnidipine exerted inhibitory effect on the growth of ESCC in the patient-derived xenograft (PDX) in vivo, which is comparable to that of trametinib. Therefore, Azelnidipine may be a valuable drug targeting MEK1/2 in the chemoprevention of ESCC progression with high MEK1/2 activity. Even more favorably, Azelnidipine is an FDA-approved drug and has no obvious toxic side effects in the clinical treatment of hypertension for a long-term use. This work deserves further attention and guarantees an immediate clinical trial in ESCC treatment. H.Q. completed the writing of the editorial. There is no conflict of interest.