The MAP kinase-interacting kinases (MNKs) as targets in oncology

ABSTRACT

Introduction: The mitogen-activated protein kinase (MAPK)-interacting kinases (MNKs) are switched on by the oncogenic MAPK (ERK) signalling pathway. They phosphorylate eukaryotic initiation factor (eIF) 4E, a protein which recruits ribosomes to mRNAs and thereby mediates their translation. Importantly, overexpression of eIF4E can transform cells, and its function is controlled by a second oncogenic pathway, mechanistic target of rapamycin complex 1.

Areas covered: We have evaluated the literature related to the role of the MNKs in human cancers, including their control by oncogenic signalling pathways; their expression and regulation in cancer cells and preclinical cancer models; and their roles in the proliferation, survival and migration/invasion of cancer cells. We also discuss progress towards generating specific and potent inhibitors of the MNKs and data obtained using such compounds.

Expert opinion: The available data indicate that MNKs and/or eIF4E phosphorylation play a role in oncogenic transformation, the progression of at least some tumours and especially in processes related to tumour metastasis. MNKs are clearly druggable targets and, as they are not essential, significant ‘side effects’ of inhibiting the MNKs are likely to be limited. Further work is required to assess the efficacy of MNK inhibition in tackling tumour development, progression and metastasis.

Trial registration: ClinicalTrials.gov identifier: NCT03616834.

KEYWORDS:

• Cancer
• eIF4E
• metastasis
• MNKs
• mRNA translation
• oncology
• transformation

Article highlights

• MAP kinase-interacting kinases (MNKs) are turned on by the oncogenic MAP kinase signalling pathway.

• Their best-known substrate, eIF4E, is encoded by a proto-oncogene and is controlled by oncogenic mTORC1 signalling.

• Phosphorylation of eIF4E likely controls the synthesis of specific proteins.

• MNKs and/or eIF4E phosphorylation can promote tumour progression and metastasis.

• MNKs are druggable targets.

• Further work is needed to probe the roles of MNKs in tumour biology and the value of targeting them for cancer therapy.

This box summarizes key points contained in the article.

Declaration of interest

Research carried out in the Proud laboratory related to the MNKs in cancer is supported by South Australian Health & Medical Research Institute. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.