Protein–Protein Interactions: Emerging Oncotargets in the RAS-ERK Pathway

García-Gómez, Rocío; Bustelo, Xosé R.; Crespo, Piero

doi:10.1016/j.trecan.2018.07.002

Cited by 52 publications

(41 citation statements)

References 90 publications

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“…In HCC patients, constitutive activation of the RAS/ERK signaling pathway promotes tumor growth, progression and recurrence [ 21 ]. Sorafenib, a RAS/ERK pathway inhibitor, is currently the most effective treatment of early and advanced HCC patients [ 22 – 24 ].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-216a-3p promotes sorafenib sensitivity in hepatocellular carcinoma by downregulating MAPK14 expression

Zhong

Liu

Wang

et al. 2020

Aging

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We investigated MAPK14-dependent resistance to sorafenib in hepatocellular carcinoma (HCC). Bioinformatics analysis and dual luciferase reporter assays in HCC cell lines showed that miR-216a-3p directly binds to the 3’UTR of MAPK14 mRNA and downregulates MAPK14 protein expression. Consequently, miR-216a-3p expression correlates inversely with MAPK14 protein levels in HCC patient tissues. miR-216a-3p overexpression significantly increases the sorafenib sensitivity of HCC cells by suppressing MAPK14 expression and reducing the subsequent activation of the MEK/ERK and ATF2 signaling pathways. The growth of xenograft tumors derived from miR-216a-3p-overexpression HCC cells was significantly diminished in sorafenib-treated Balb/c nude mice compared to controls. High miR-216a-3p levels in HCC tissue samples prior to treatment correlated with a better sorafenib response and favorable prognosis. Our findings thus demonstrate that miR-216a-3p enhances sorafenib sensitivity in HCC cells and tumor tissues by decreasing MAPK14 levels, thereby inhibiting the MAPK14-dependent MEK/ERK and ATF2 signaling.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-216a-3p promotes sorafenib sensitivity in hepatocellular carcinoma by downregulating MAPK14 expression

Zhong

Liu

Wang

et al. 2020

Aging

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“…Inhibition of PPIs, particularly using peptides, is currently a hot area of pharmaceutical research. For the RAS/MAPK pathway alone, at least 30 inhibitors of PPI have been developed and several of them are undergoing clinical trials [García-Gómez 2018]. However, no studies on SHP2 have been reported, notwithstanding the central role of this phosphatase in the pathway.…”

Section: Discussionmentioning

confidence: 99%

Targeting Oncogenic Src Homology 2 Domain-Containing Phosphatase 2 (SHP2) by Inhibiting its Protein-Protein Interactions

Bobone

Pannone

Biondi

et al. 2020

Preprint

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Mutations of PTPN11, the gene coding for the Src homology 2 domain-containing phosphatase 2 (SHP2), cause childhood leukemias and developmental disorders. SHP2 inhibitors targeting the catalytic site or an allosteric pocket lack specificity or are ineffective on pathogenic variants. In addition, several data indicate that increased association with cognate proteins, through its SH2 domains, rather than enhanced catalytic activity, is the main effect of mutations causing hyperactivation of SHP2-mediated signaling. We developed peptide-based molecules with low nM affinity to the N-SH2 domain and high specificity. These molecules bind to pathogenic variants of SHP2 with an affinity up to 20 times higher than to the wild-type protein, in contrast to allosteric inhibitors, and were able to revert the effects of a pathogenic SHP2 mutation in zebrafish embryos. Our results provide a novel route for SHP2-targeted therapies and a tool to investigate the role of protein-protein interactions in the function of SHP2.TABLE OF CONTENTS GRAPHICS

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“…A variety of compounds that inhibit different components of the RAS/ERK cascade have reached clinical trials for the treatment of specific types of cancer, such as PD184352 (MEK1/2 inhibitor) and Ulixertinib (ERK1/2 inhibitor), while others have already gained approval, as is the case of Trametinib, inhibitor of MEK1/2, for BRAF-mutant melanoma (Ref. 139). The experience in drug discovery obtained through years of research on this molecular pathway holds promise for a potential therapeutic application in craniofacial disorders (Ref.…”

Section: Discussionmentioning

confidence: 99%

Craniofacial, orofacial and dental disorders: the role of the RAS/ERK pathway

Vogiatzi

Mavrothalassitis

2019

Expert Rev. Mol. Med.

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Deviations from the precisely coordinated programme of human head development can lead to craniofacial and orofacial malformations often including a variety of dental abnormalities too. Although the aetiology is still unknown in many cases, during the last decades different intracellular signalling pathways have been genetically linked to specific disorders. Among these pathways, the RAS/extracellular signal-regulated kinase (ERK) signalling cascade is the focus of this review since it encompasses a large group of genes that when mutated cause some of the most common and severe developmental anomalies in humans. We present the components of the RAS/ERK pathway implicated in craniofacial and orodental disorders through a series of human and animal studies. We attempt to unravel the specific molecular targets downstream of ERK that act on particular cell types and regulate key steps in the associated developmental processes. Finally we point to ambiguities in our current knowledge that need to be clarified before RAS/ERK-targeting therapeutic approaches can be implemented.

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Protein–Protein Interactions: Emerging Oncotargets in the RAS-ERK Pathway

Cited by 52 publications

References 90 publications

MicroRNA-216a-3p promotes sorafenib sensitivity in hepatocellular carcinoma by downregulating MAPK14 expression

MicroRNA-216a-3p promotes sorafenib sensitivity in hepatocellular carcinoma by downregulating MAPK14 expression

Targeting Oncogenic Src Homology 2 Domain-Containing Phosphatase 2 (SHP2) by Inhibiting its Protein-Protein Interactions

Craniofacial, orofacial and dental disorders: the role of the RAS/ERK pathway

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