Targeting RAS phosphorylation in cancer therapy: Mechanisms and modulators

RAS, a member of the small GTPase family, functions as a binary switch by shifting between inactive GDP-loaded and active GTP-loaded state. RAS gain-of-function mutations are one of the leading causes in human oncogenesis, accounting for ∼19% of the global cancer burden. As a well-recognized target...

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Autores principales:	Yuran Qiu, Yuanhao Wang, Zongtao Chai, Duan Ni, Xinyi Li, Jun Pu, Jie Chen, Jian Zhang, Shaoyong Lu, Chuan Lv, Mingfei Ji
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	RAS Phosphorylation Undruggable Protein kinases Allostery Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/0f94c0b405394554beaf7fb7464520c3
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spelling	oai:doaj.org-article:0f94c0b405394554beaf7fb7464520c32021-12-02T05:01:19ZTargeting RAS phosphorylation in cancer therapy: Mechanisms and modulators2211-383510.1016/j.apsb.2021.02.014https://doaj.org/article/0f94c0b405394554beaf7fb7464520c32021-11-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2211383521000629https://doaj.org/toc/2211-3835RAS, a member of the small GTPase family, functions as a binary switch by shifting between inactive GDP-loaded and active GTP-loaded state. RAS gain-of-function mutations are one of the leading causes in human oncogenesis, accounting for ∼19% of the global cancer burden. As a well-recognized target in malignancy, RAS has been intensively studied in the past decades. Despite the sustained efforts, many failures occurred in the earlier exploration and resulted in an ‘undruggable’ feature of RAS proteins. Phosphorylation at several residues has been recently determined as regulators for wild-type and mutated RAS proteins. Therefore, the development of RAS inhibitors directly targeting the RAS mutants or towards upstream regulatory kinases supplies a novel direction for tackling the anti-RAS difficulties. A better understanding of RAS phosphorylation can contribute to future therapeutic strategies. In this review, we comprehensively summarized the current advances in RAS phosphorylation and provided mechanistic insights into the signaling transduction of associated pathways. Importantly, the preclinical and clinical success in developing anti-RAS drugs targeting the upstream kinases and potential directions of harnessing allostery to target RAS phosphorylation sites were also discussed.Yuran QiuYuanhao WangZongtao ChaiDuan NiXinyi LiJun PuJie ChenJian ZhangShaoyong LuChuan LvMingfei JiElsevierarticleRASPhosphorylationUndruggableProtein kinasesAllosteryTherapeutics. PharmacologyRM1-950ENActa Pharmaceutica Sinica B, Vol 11, Iss 11, Pp 3433-3446 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	RAS Phosphorylation Undruggable Protein kinases Allostery Therapeutics. Pharmacology RM1-950
spellingShingle	RAS Phosphorylation Undruggable Protein kinases Allostery Therapeutics. Pharmacology RM1-950 Yuran Qiu Yuanhao Wang Zongtao Chai Duan Ni Xinyi Li Jun Pu Jie Chen Jian Zhang Shaoyong Lu Chuan Lv Mingfei Ji Targeting RAS phosphorylation in cancer therapy: Mechanisms and modulators
description	RAS, a member of the small GTPase family, functions as a binary switch by shifting between inactive GDP-loaded and active GTP-loaded state. RAS gain-of-function mutations are one of the leading causes in human oncogenesis, accounting for ∼19% of the global cancer burden. As a well-recognized target in malignancy, RAS has been intensively studied in the past decades. Despite the sustained efforts, many failures occurred in the earlier exploration and resulted in an ‘undruggable’ feature of RAS proteins. Phosphorylation at several residues has been recently determined as regulators for wild-type and mutated RAS proteins. Therefore, the development of RAS inhibitors directly targeting the RAS mutants or towards upstream regulatory kinases supplies a novel direction for tackling the anti-RAS difficulties. A better understanding of RAS phosphorylation can contribute to future therapeutic strategies. In this review, we comprehensively summarized the current advances in RAS phosphorylation and provided mechanistic insights into the signaling transduction of associated pathways. Importantly, the preclinical and clinical success in developing anti-RAS drugs targeting the upstream kinases and potential directions of harnessing allostery to target RAS phosphorylation sites were also discussed.
format	article
author	Yuran Qiu Yuanhao Wang Zongtao Chai Duan Ni Xinyi Li Jun Pu Jie Chen Jian Zhang Shaoyong Lu Chuan Lv Mingfei Ji
author_facet	Yuran Qiu Yuanhao Wang Zongtao Chai Duan Ni Xinyi Li Jun Pu Jie Chen Jian Zhang Shaoyong Lu Chuan Lv Mingfei Ji
author_sort	Yuran Qiu
title	Targeting RAS phosphorylation in cancer therapy: Mechanisms and modulators
title_short	Targeting RAS phosphorylation in cancer therapy: Mechanisms and modulators
title_full	Targeting RAS phosphorylation in cancer therapy: Mechanisms and modulators
title_fullStr	Targeting RAS phosphorylation in cancer therapy: Mechanisms and modulators
title_full_unstemmed	Targeting RAS phosphorylation in cancer therapy: Mechanisms and modulators
title_sort	targeting ras phosphorylation in cancer therapy: mechanisms and modulators
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/0f94c0b405394554beaf7fb7464520c3
work_keys_str_mv	AT yuranqiu targetingrasphosphorylationincancertherapymechanismsandmodulators AT yuanhaowang targetingrasphosphorylationincancertherapymechanismsandmodulators AT zongtaochai targetingrasphosphorylationincancertherapymechanismsandmodulators AT duanni targetingrasphosphorylationincancertherapymechanismsandmodulators AT xinyili targetingrasphosphorylationincancertherapymechanismsandmodulators AT junpu targetingrasphosphorylationincancertherapymechanismsandmodulators AT jiechen targetingrasphosphorylationincancertherapymechanismsandmodulators AT jianzhang targetingrasphosphorylationincancertherapymechanismsandmodulators AT shaoyonglu targetingrasphosphorylationincancertherapymechanismsandmodulators AT chuanlv targetingrasphosphorylationincancertherapymechanismsandmodulators AT mingfeiji targetingrasphosphorylationincancertherapymechanismsandmodulators
_version_	1718400812505366528

Targeting RAS phosphorylation in cancer therapy: Mechanisms and modulators

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