The ERK5 pathway in BRAFV600E melanoma cells plays a role in development of acquired resistance to dabrafenib but not vemurafenib

被引：6

作者：

Mondru, Anil Kumar ^{[1
]}

Wilkinson, Beth ^{[1
]}

Aljasir, Mohammad A. ^{[1
,3
]}

Alrumayh, Ahmed ^{[1
]}

Greaves, Georgia ^{[1
]}

Emmett, Maxine ^{[1
]}

Albohairi, Saad ^{[1
]}

Pritchard-Jones, Rowan ^{[2
]}

Cross, Michael J. ^{[1
]}

机构：

[1] Univ Liverpool, Dept Pharmacol & Therapeut, Inst Syst Mol & Integrat Biol, Liverpool, England

[2] Univ Liverpool, Inst Syst Mol & Integrat Biol, Dept Mol & Clin Canc Med, Liverpool, England

[3] Qassim Univ, Coll Appl Med Sci, Dept Med Labs, Buraydah 52571, Saudi Arabia

来源：

FEBS LETTERS | 2024年 / 598卷 / 16期

基金：

英国惠康基金;

关键词：

BRAF; dabrafenib; drug-resistance; ERK5; melanoma; vemurafenib; SIGNALING PATHWAY; CYCLIN D1; B-RAF; INHIBITION; BRAF; SUPPRESSION; ACTIVATION; MUTATIONS; MECHANISM; SURVIVAL;

D O I：

10.1002/1873-3468.14960

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Malignant melanoma, an aggressive skin cancer with a poor prognosis, frequently features BRAFV600E mutation resulting in activation of the MAPK pathway and melanocyte proliferation and survival. BRAFV600E inhibitors like vemurafenib and dabrafenib have enhanced patient survival, yet drug resistance remains a significant challenge. We investigated the role of the ERK5 pathway in BRAFV600E melanoma cells and cells with acquired resistance to PLX4720 (vemurafenib) and dabrafenib. In BRAFV600E melanoma, ERK5 inhibition minimally affected viability compared to ERK1/2 inhibition. In vemurafenib-resistant cells, ERK5 inhibition alone didn't impact viability or restore drug sensitivity to vemurafenib. However, in dabrafenib-resistant cells, ERK5 inhibition reduced viability and enhanced the anti-proliferative effect of MEK1/2 inhibition. Targeting the ERK5 pathway may represent a therapeutic opportunity in dabrafenib-resistant melanoma.

引用

页码：2011 / 2027

页数：17

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