The MAPK and AMPK signalings: interplay and implication in targeted cancer therapy

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Abstract

Cancer is characterized as a complex disease caused by coordinated alterations of multiple signaling pathways. The Ras/RAF/MEK/ERK (MAPK) signaling is one of the best-defined pathways in cancer biology, and its hyperactivation is responsible for over 40% human cancer cases. To drive carcinogenesis, this signaling promotes cellular overgrowth by turning on proliferative genes, and simultaneously enables cells to overcome metabolic stress by inhibiting AMPK signaling, a key singular node of cellular metabolism. Recent studies have shown that AMPK signaling can also reversibly regulate hyperactive MAPK signaling in cancer cells by phosphorylating its key components, RAF/KSR family kinases, which affects not only carcinogenesis but also the outcomes of targeted cancer therapies against the MAPK signaling. In this review, we will summarize the current proceedings of how MAPK-AMPK signalings interplay with each other in cancer biology, as well as its implications in clinic cancer treatment with MAPK inhibition and AMPK modulators, and discuss the exploitation of combinatory therapies targeting both MAPK and AMPK as a novel therapeutic intervention.

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Most cited references 182

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Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal.

J. Gao, B. A. Aksoy, U Dogrusoz … (2015)

The cBioPortal for Cancer Genomics (http://cbioportal.org) provides a Web resource for exploring, visualizing, and analyzing multidimensional cancer genomics data. The portal reduces molecular profiling data from cancer tissues and cell lines into readily understandable genetic, epigenetic, gene expression, and proteomic events. The query interface combined with customized data storage enables researchers to interactively explore genetic alterations across samples, genes, and pathways and, when available in the underlying data, to link these to clinical outcomes. The portal provides graphical summaries of gene-level data from multiple platforms, network visualization and analysis, survival analysis, patient-centric queries, and software programmatic access. The intuitive Web interface of the portal makes complex cancer genomics profiles accessible to researchers and clinicians without requiring bioinformatics expertise, thus facilitating biological discoveries. Here, we provide a practical guide to the analysis and visualization features of the cBioPortal for Cancer Genomics.

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Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation.

Ramin Nazarian, Hubing Shi, Qi Wang … (2010)

Activating B-RAF(V600E) (also known as BRAF) kinase mutations occur in ∼7% of human malignancies and ∼60% of melanomas. Early clinical experience with a novel class I RAF-selective inhibitor, PLX4032, demonstrated an unprecedented 80% anti-tumour response rate among patients with B-RAF(V600E)-positive melanomas, but acquired drug resistance frequently develops after initial responses. Hypotheses for mechanisms of acquired resistance to B-RAF inhibition include secondary mutations in B-RAF(V600E), MAPK reactivation, and activation of alternative survival pathways. Here we show that acquired resistance to PLX4032 develops by mutually exclusive PDGFRβ (also known as PDGFRB) upregulation or N-RAS (also known as NRAS) mutations but not through secondary mutations in B-RAF(V600E). We used PLX4032-resistant sub-lines artificially derived from B-RAF(V600E)-positive melanoma cell lines and validated key findings in PLX4032-resistant tumours and tumour-matched, short-term cultures from clinical trial patients. Induction of PDGFRβ RNA, protein and tyrosine phosphorylation emerged as a dominant feature of acquired PLX4032 resistance in a subset of melanoma sub-lines, patient-derived biopsies and short-term cultures. PDGFRβ-upregulated tumour cells have low activated RAS levels and, when treated with PLX4032, do not reactivate the MAPK pathway significantly. In another subset, high levels of activated N-RAS resulting from mutations lead to significant MAPK pathway reactivation upon PLX4032 treatment. Knockdown of PDGFRβ or N-RAS reduced growth of the respective PLX4032-resistant subsets. Overexpression of PDGFRβ or N-RAS(Q61K) conferred PLX4032 resistance to PLX4032-sensitive parental cell lines. Importantly, MAPK reactivation predicts MEK inhibitor sensitivity. Thus, melanomas escape B-RAF(V600E) targeting not through secondary B-RAF(V600E) mutations but via receptor tyrosine kinase (RTK)-mediated activation of alternative survival pathway(s) or activated RAS-mediated reactivation of the MAPK pathway, suggesting additional therapeutic strategies.

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Combined vemurafenib and cobimetinib in BRAF-mutated melanoma.

James Larkin, Paolo Ascierto, Brigitte Dréno … (2014)

The combined inhibition of BRAF and MEK is hypothesized to improve clinical outcomes in patients with melanoma by preventing or delaying the onset of resistance observed with BRAF inhibitors alone. This randomized phase 3 study evaluated the combination of the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib. We randomly assigned 495 patients with previously untreated unresectable locally advanced or metastatic BRAF V600 mutation-positive melanoma to receive vemurafenib and cobimetinib (combination group) or vemurafenib and placebo (control group). The primary end point was investigator-assessed progression-free survival. The median progression-free survival was 9.9 months in the combination group and 6.2 months in the control group (hazard ratio for death or disease progression, 0.51; 95% confidence interval [CI], 0.39 to 0.68; P<0.001). The rate of complete or partial response in the combination group was 68%, as compared with 45% in the control group (P<0.001), including rates of complete response of 10% in the combination group and 4% in the control group. Progression-free survival as assessed by independent review was similar to investigator-assessed progression-free survival. Interim analyses of overall survival showed 9-month survival rates of 81% (95% CI, 75 to 87) in the combination group and 73% (95% CI, 65 to 80) in the control group. Vemurafenib and cobimetinib was associated with a nonsignificantly higher incidence of adverse events of grade 3 or higher, as compared with vemurafenib and placebo (65% vs. 59%), and there was no significant difference in the rate of study-drug discontinuation. The number of secondary cutaneous cancers decreased with the combination therapy. The addition of cobimetinib to vemurafenib was associated with a significant improvement in progression-free survival among patients with BRAF V600-mutated metastatic melanoma, at the cost of some increase in toxicity. (Funded by F. Hoffmann-La Roche/Genentech; coBRIM ClinicalTrials.gov number, NCT01689519.).

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Author and article information

Contributors

Jimin Yuan: yuan.jimin@szhospital.com

Jiancheng Hu:

ORCID: http://orcid.org/0000-0003-1615-0030

hu.jiancheng@nccs.com.sg

Journal

Journal ID (nlm-ta): J Hematol Oncol

Journal ID (iso-abbrev): J Hematol Oncol

Title: Journal of Hematology & Oncology

Publisher: BioMed Central (London )

ISSN (Electronic): 1756-8722

Publication date (Electronic): 17 August 2020

Publication date PMC-release: 17 August 2020

Publication date Collection: 2020

Volume: 13

Electronic Location Identifier: 113

Affiliations

[1 ]GRID grid.440218.b, ISNI 0000 0004 1759 7210, Department of Urology, , Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), ; Shenzhen, 518020 Guangdong China

[2 ]GRID grid.440218.b, ISNI 0000 0004 1759 7210, Geriatric Department, , Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), ; Shenzhen, 518020 Guangdong China

[3 ]GRID grid.440218.b, ISNI 0000 0004 1759 7210, Shenzhen People’s Hospital, ; 1017 Dongmen North Road, Shenzhen, 518020 China

[4 ]GRID grid.428397.3, ISNI 0000 0004 0385 0924, Cancer and Stem Cell Program, , Duke-NUS Medical School, ; 8 College Road, Singapore, 169857 Singapore

[5 ]GRID grid.410724.4, ISNI 0000 0004 0620 9745, Division of Cellular and Molecular Research, , National Cancer Centre Singapore, ; 11 Hospital Drive, Singapore, 169610 Singapore

Author information

Jiancheng Hu http://orcid.org/0000-0003-1615-0030

Article

Publisher ID: 949

DOI: 10.1186/s13045-020-00949-4

PMC ID: 7433213

PubMed ID: 32807225

SO-VID: 82b832f0-379a-48b4-96ae-2141c648043a

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 3 June 2020

Date accepted : 4 August 2020

Funding

Funded by: Asia Fund for Cancer Research

Award ID: AFCR-2017/2019-JH

Award Recipient : Jiancheng Hu

Funded by: SingHealth Foundation

Award ID: AM/TP011/2018

Award Recipient : Jiancheng Hu

Funded by: FundRef http://dx.doi.org/10.13039/501100001349, National Medical Research Council;

Award ID: OFIRG18nov-0078

Award Recipient : Jiancheng Hu

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: ras/raf/mek/erk signaling,ampk signaling,interplay,tumorigenesis,cellular metabolism,raf/mek/erk inhibitors,ampk inhibitors,ampk activators,autophagy,targeted therapy

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: ras/raf/mek/erk signaling, ampk signaling, interplay, tumorigenesis, cellular metabolism, raf/mek/erk inhibitors, ampk inhibitors, ampk activators, autophagy, targeted therapy

The MAPK and AMPK signalings: interplay and implication in targeted cancer therapy

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Karger: Oncology

Most cited references 182

Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal.

Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation.

Combined vemurafenib and cobimetinib in BRAF-mutated melanoma.

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