Targeting the MAPK–RAS–RAF signaling pathway in cancer therapy
TL;DR: Inhibitors of MEK and particularly of RAF kinases have shown effectiveness in clinical trials with manageable side effects and need to be analyzed for mutations as markers of response to treatments and to avoid paradoxical effects.
Abstract: Introduction: The MAPK pathway comprises several key signaling components and phosphorylation events that play a role in tumorigenesis. These activated kinases transmit extracellular signals that regulate cell growth, differentiation, proliferation, apoptosis and migration functions. Alteration of the RAS–RAF–MEK–ERK–MAPK (RAS–MAPK) pathway has been reported in human cancer as a result of abnormal activation of receptor tyrosine kinases or gain-of-function mutations mainly in the RAS or RAF genes. These pathways are considered potential therapeutic targets for cancer treatment. Recently, several small-molecule inhibitors targeting this pathway have been developed and are currently being tested in clinical trials. Areas covered: The biological role of the RAS–MAPK pathway, the consequence of its disregulation and the development of small-molecule inhibitors. The rationale for targeting the RAS–MAPK pathway and the application and the results of various inhibitory molecules as anticancer agents in clinical ...
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TL;DR: A comprehensive review of small-molecule targeted anti-cancer drugs according to the target classification is conducted, which presents all the approved drugs as well as important drug candidates in clinical trials for each target, and discusses the current challenges.
Abstract: Due to the advantages in efficacy and safety compared with traditional chemotherapy drugs, targeted therapeutic drugs have become mainstream cancer treatments. Since the first tyrosine kinase inhibitor imatinib was approved to enter the market by the US Food and Drug Administration (FDA) in 2001, an increasing number of small-molecule targeted drugs have been developed for the treatment of malignancies. By December 2020, 89 small-molecule targeted antitumor drugs have been approved by the US FDA and the National Medical Products Administration (NMPA) of China. Despite great progress, small-molecule targeted anti-cancer drugs still face many challenges, such as a low response rate and drug resistance. To better promote the development of targeted anti-cancer drugs, we conducted a comprehensive review of small-molecule targeted anti-cancer drugs according to the target classification. We present all the approved drugs as well as important drug candidates in clinical trials for each target, discuss the current challenges, and provide insights and perspectives for the research and development of anti-cancer drugs.
398 citations
TL;DR: Progress in in vitro screening platforms as well as orthotopic and 'orthometastatic' xenograft mouse models has enabled comprehensive characterization of the impact of the tumour microenvironment on therapeutic efficacy, which can hopefully bridge the gap between preclinical studies and clinical trials of anticancer agents.
Abstract: The role of stromal cells and the tumour microenvironment in general in modulating tumour sensitivity is increasingly becoming a key consideration for the development of active anticancer therapeutics. Here, we discuss how these tumour-stromal interactions affect tumour cell signalling, survival, proliferation and drug sensitivity. Particular emphasis is placed on the ability of stromal cells to confer - to tumour cells - resistance or sensitization to different classes of therapeutics, depending on the specific microenvironmental context. The mechanistic understanding of these microenvironmental interactions can influence the evaluation and selection of candidate agents for various cancers, in both the primary site as well as the metastatic setting. Progress in in vitro screening platforms as well as orthotopic and 'orthometastatic' xenograft mouse models has enabled comprehensive characterization of the impact of the tumour microenvironment on therapeutic efficacy. These recent advances can hopefully bridge the gap between preclinical studies and clinical trials of anticancer agents.
395 citations
TL;DR: Overexpression of ciRS-7 in HCT116 and HT29 cells led to the blocking of miR-7 and resulted in a more aggressive oncogenic phenotype, and ci RS-7 overexpression permitted the inhibition of mi R7 and subsequent activation of EGFR and RAF1 oncogenes.
Abstract: Purpose: Colorectal cancer is one of the most common malignancies worldwide. Recently, a novel circular RNA, ciRS-7, was proposed to be a potential miR-7 sponge. As miR-7, a putative tumor-suppressor, regulates the expression of several important drivers of colorectal cancer, we analyzed the clinical significance of ciRS-7 in colorectal cancer patients.Experimental Design: Initially, we evaluated the expression levels of ciRS-7 in a training cohort comprising of 153 primary colorectal cancer tissues and 44 matched normal mucosae. We subsequently confirmed its clinical relevance in an independent validation cohort (n = 165), and evaluated the effect of ciRS-7 on miR-7, and its target genes EGFR and RAF1. Functional analyses were performed in cell lines and an animal model to support clinical findings.Results: Our data revealed that ciRS-7 was significantly upregulated in colorectal cancer tissues compared with matched normal mucosae (P = 0.0018), and its overexpression was associated with poor patient survival (P = 0.0224 and 0.0061 in the training and validation cohorts, respectively). Multivariate survival analysis revealed that ciRS-7 emerged as an independent risk factor for overall survival (P = 0.0656 and 0.0324 in the training and validation cohorts, respectively). Overexpression of ciRS-7 in HCT116 and HT29 cells led to the blocking of miR-7 and resulted in a more aggressive oncogenic phenotype, and ciRS-7 overexpression permitted the inhibition of miR-7 and subsequent activation of EGFR and RAF1 oncogenes.Conclusions: CiRS-7 is a promising prognostic biomarker in colorectal cancer patients and may serve as a therapeutic target for reducing EGFR-RAF1 activity in colorectal cancer patients. Clin Cancer Res; 23(14); 3918-28. ©2017 AACR.
360 citations
Cites background from "Targeting the MAPK–RAS–RAF signalin..."
...RAF1, similar to BRAF, contributes to activation of MAPK pathway, but is rarely mutated in colorectal cancer (42), and a recent study showed inhibition of RAF1 as a promising therapeutic strategy for BRAF- and KRAS-mutant cancers (43)....
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TL;DR: This work focuses on the mechanisms how stress activated MAPK pathways, such as p38 MAPK and the Jun N-terminal kinases (JNK), impact the response of cancer cells to chemotherapies and targeted therapies.
Abstract: Mitogen-activated protein kinase (MAPK) pathways represent ubiquitous signal transduction pathways that regulate all aspects of life and are frequently altered in disease. Here, we focus on the role of MAPK pathways in modulating drug sensitivity and resistance in cancer. We briefly discuss new findings in the extracellular signaling-regulated kinase (ERK) pathway, but mainly focus on the mechanisms how stress activated MAPK pathways, such as p38 MAPK and the Jun N-terminal kinases (JNK), impact the response of cancer cells to chemotherapies and targeted therapies. In this context, we also discuss the role of metabolic and epigenetic aberrations and new therapeutic opportunities arising from these changes.
339 citations
Cites background from "Targeting the MAPK–RAS–RAF signalin..."
...Most of the seminal work was done in metastatic malignant melanoma, which is hallmarked by a high prevalence of BRAF (50–60%) and NRAS (15–20%) mutations [14]....
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...The RAS-RAF-MEK-ERK pathway is altered in ~40% of all human cancers, mainly due to mutations in BRAF (~10%) and its upstream activator RAS (~30%) [14]....
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TL;DR: In this review, strategies used to overcome peptide limitations and to enhance their therapeutic effect will be compared and the use of short cell permeable peptides that interfere and inhibit protein-protein interactions will be evaluated.
Abstract: Cancer along with cardiovascular disease are the main causes of death in the industrialised countries around the World. Conventional cancer treatments are losing their therapeutic uses due to drug resistance, lack of tumour selectivity and solubility and as such there is a need to develop new therapeutic agents. Therapeutic peptides are a promising and a novel approach to treat many diseases including cancer. They have several advantages over proteins or antibodies: as they are (a) easy to synthesise, (b) have a high target specificity and selectivity and (c) have low toxicity. Therapeutic peptides do have some significant drawbacks related to their stability and short half-life. In this review, strategies used to overcome peptide limitations and to enhance their therapeutic effect will be compared. The use of short cell permeable peptides that interfere and inhibit protein-protein interactions will also be evaluated.
337 citations
Cites background from "Targeting the MAPK–RAS–RAF signalin..."
...Developing small molecule inhibitors that target the Ras/Raf/MEK/ERK pathway has great potential for cancer therapy [103]....
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References
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TL;DR: BRAF somatic missense mutations in 66% of malignant melanomas and at lower frequency in a wide range of human cancers, with a single substitution (V599E) accounting for 80%.
Abstract: Cancers arise owing to the accumulation of mutations in critical genes that alter normal programmes of cell proliferation, differentiation and death. As the first stage of a systematic genome-wide screen for these genes, we have prioritized for analysis signalling pathways in which at least one gene is mutated in human cancer. The RAS RAF MEK ERK MAP kinase pathway mediates cellular responses to growth signals. RAS is mutated to an oncogenic form in about 15% of human cancer. The three RAF genes code for cytoplasmic serine/threonine kinases that are regulated by binding RAS. Here we report BRAF somatic missense mutations in 66% of malignant melanomas and at lower frequency in a wide range of human cancers. All mutations are within the kinase domain, with a single substitution (V599E) accounting for 80%. Mutated BRAF proteins have elevated kinase activity and are transforming in NIH3T3 cells. Furthermore, RAS function is not required for the growth of cancer cell lines with the V599E mutation. As BRAF is a serine/threonine kinase that is commonly activated by somatic point mutation in human cancer, it may provide new therapeutic opportunities in malignant melanoma.
9,785 citations
"Targeting the MAPK–RAS–RAF signalin..." refers background in this paper
...BRAF is frequently mutated in a variety of human tumors, especially in malignant melanoma, thyroid and colon carcinomas (Table 2) [34]....
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Memorial Sloan Kettering Cancer Center1, University of Kiel2, Institut Gustave Roussy3, Netherlands Cancer Institute4, The Royal Marsden NHS Foundation Trust5, University of Zurich6, University of Tübingen7, University of Manchester8, University of Paris9, University of Duisburg-Essen10, University of California, Los Angeles11, Vanderbilt University12, University of Pittsburgh13, University of Nantes14, Plexxikon15, Hoffmann-La Roche16, Genentech17, Harvard University18, Peter MacCallum Cancer Centre19
TL;DR: Vemurafenib produced improved rates of overall and progression-free survival in patients with previously untreated melanoma with the BRAF V600E mutation in a phase 3 randomized clinical trial.
Abstract: At 6 months, overall survival was 84% (95% confidence interval [CI], 78 to 89) in the vemurafenib group and 64% (95% CI, 56 to 73) in the dacarbazine group. In the interim analysis for overall survival and final analysis for progression-free survival, vemurafenib was associated with a relative reduction of 63% in the risk of death and of 74% in the risk of either death or disease progression, as compared with dacarbazine (P<0.001 for both comparisons). After review of the interim analysis by an independent data and safety monitoring board, crossover from dacarbazine to vemurafenib was recommended. Response rates were 48% for vemurafenib and 5% for dacarbazine. Common adverse events associated with vemurafenib were arthralgia, rash, fatigue, alopecia, keratoacanthoma or squamous-cell carcinoma, photosensitivity, nausea, and diarrhea; 38% of patients required dose modification because of toxic effects. Conclusions Vemurafenib produced improved rates of overall and progression-free survival in patients with previously untreated melanoma with the BRAF V600E mutation. (Funded by Hoffmann–La Roche; BRIM-3 ClinicalTrials.gov number, NCT01006980.)
6,773 citations
TL;DR: Nonenzymatic mechanisms that impact MAP kinase functions and findings from gene disruption studies are highlighted and particular emphasis is on ERK1/2.
Abstract: Mitogen-activated protein (MAP) kinases comprise a family of ubiquitous proline-directed, protein-serine/threonine kinases, which participate in signal transduction pathways that control intracellular events including acute responses to hormones and major developmental changes in organisms. MAP kinases lie in protein kinase cascades. This review discusses the regulation and functions of mammalian MAP kinases. Nonenzymatic mechanisms that impact MAP kinase functions and findings from gene disruption studies are highlighted. Particular emphasis is on ERK1/2.
4,040 citations
"Targeting the MAPK–RAS–RAF signalin..." refers background in this paper
...In contrast, moderate levels of MAPK pathway activation may induce abnormal cellular functions [42]....
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TL;DR: Data demonstrate that BAY 43-9006 is a novel dual action RAF kinase and VEGFR inhibitor that targets tumor cell proliferation and tumor angiogenesis.
Abstract: The RAS/RAF signaling pathway is an important mediator of tumor cell proliferation and angiogenesis. The novel bi-aryl urea BAY 43-9006 is a potent inhibitor of Raf-1, a member of the RAF/MEK/ERK signaling pathway. Additional characterization showed that BAY 43-9006 suppresses both wild-type and V599E mutant BRAF activity in vitro. In addition, BAY 43-9006 demonstrated significant activity against several receptor tyrosine kinases involved in neovascularization and tumor progression, including vascular endothelial growth factor receptor (VEGFR)-2, VEGFR-3, platelet-derived growth factor receptor beta, Flt-3, and c-KIT. In cellular mechanistic assays, BAY 43-9006 demonstrated inhibition of the mitogen-activated protein kinase pathway in colon, pancreatic, and breast tumor cell lines expressing mutant KRAS or wild-type or mutant BRAF, whereas non-small-cell lung cancer cell lines expressing mutant KRAS were insensitive to inhibition of the mitogen-activated protein kinase pathway by BAY 43-9006. Potent inhibition of VEGFR-2, platelet-derived growth factor receptor beta, and VEGFR-3 cellular receptor autophosphorylation was also observed for BAY 43-9006. Once daily oral dosing of BAY 43-9006 demonstrated broad-spectrum antitumor activity in colon, breast, and non-small-cell lung cancer xenograft models. Immunohistochemistry demonstrated a close association between inhibition of tumor growth and inhibition of the extracellular signal-regulated kinases (ERKs) 1/2 phosphorylation in two of three xenograft models examined, consistent with inhibition of the RAF/MEK/ERK pathway in some but not all models. Additional analyses of microvessel density and microvessel area in the same tumor sections using antimurine CD31 antibodies demonstrated significant inhibition of neovascularization in all three of the xenograft models. These data demonstrate that BAY 43-9006 is a novel dual action RAF kinase and VEGFR inhibitor that targets tumor cell proliferation and tumor angiogenesis.
3,749 citations
"Targeting the MAPK–RAS–RAF signalin..." refers background in this paper
...The RAF family members, (A-Raf, B-Raf, and C-Raf or Raf-1), are highly conserved serine/threonine kinases of the MAPK [RAS--RAF--MEK--ERK] pathway (Figure 2)....
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...ISIS-5132, a 20-base phosphorothioate DNA oligonucleotide, blocks mainly c-Raf-1 protein expression and showed antitumor activity in preclinical xenograph models and early clinical trials....
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...Sorafenib is a bi-aryl urea compound that was originally developed as an inhibitor of Raf-1 [77]....
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...Subsequent studies revealed that sorafenib is also a potent inhibitor of both wild-type and mutant B-Raf V600E kinases in vitro, and has a potent activity for other protein kinases, such as, the proangiogenic tyrosine kinase receptors and VEGFR-2, VEGFR-3, fibroblast growth ractor receptor 1 (FGFR-1), platelet-derived growth factor receptor b (PDGFR-b), McDonough feline sarcoma viral oncogene-like tyrosine kinase 3 (Flt-3), and c-Kit [77]....
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...AZ628 is a selective RAF inhibitor of CRAF (Raf-1) as well as BRAF wild type and the V600E BRAF....
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TL;DR: The results indicate that the activation of Raf is suppressed and that its inactivation is accelerated by a downstream component(s) of the MAP kinase pathway.
3,444 citations
"Targeting the MAPK–RAS–RAF signalin..." refers background in this paper
...inhibitory effects when tested against a panel of other serine/ threonine kinases [48]....
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