Genentech Oncology
The mitogen-activated protein kinase (MAPK) pathway plays a role in the regulation of gene expression, cellular growth, and survival.1 Abnormal MAPK signaling may lead to increased or uncontrolled cell proliferation and resistance to apoptosis.2
Research into the MAPK pathway has shown it to be important in some cancers.2 Based on these findings, we are investigating further ways to impact MAPK signaling.
The mitogen-activated protein kinase (MAPK) pathway includes the signaling molecules Ras, Raf, MEK, and ERK. Normally, extracellular growth factors activate the pathway by binding to receptor tyrosine kinases. This mobilizes a cascade of signaling via the MAPK pathway signaling molecules. Ultimately, activation of the MAPK pathway leads to the transcription of genes that encode proteins involved in the regulation of essential cellular functions, such as cell growth, cell proliferation, and cell differentiation.1,3
First: MAPK signaling begins with the activation of the protein Ras by receptor tyrosine kinases.1
Activated Ras causes the membrane recruitment and activation of Raf proteins.3
Then: Raf phosphorylates MEK, a separate protein kinase in the pathway.1-3
Next: MEK phosphorylates ERK, which can directly and indirectly activate many transcription factors.1,4
Finally: The activation of these transcription factors by ERK leads to the expression of genes encoding proteins that regulate cell proliferation and survival.2,4
Dysregulated MAPK signaling is implicated in a wide range of cancers and occurs via multiple mechanisms, including abnormal expression of pathway receptors and/or genetic mutations that lead to activation of receptors and downstream signaling molecules in the absence of appropriate stimuli.2,5
Mutated BRAF molecules signal independently of upstream cues, leading to overactive downstream signaling via MEK and ERK.9,10 This dysregulated signaling results in excessive cell proliferation and survival, independent of growth factors, and may play a role in specific malignancies.2,10
These involve the substitution of glutamic acid (E) for valine (V) at position V600 of the protein chain, resulting in constitutively active BRAF. Other variants of this point mutation include lysine (K), aspartic acid (D), and arginine (R). The V600 point mutation allows BRAF to signal independently of upstream cues.11
Overactivation of MAPK signaling by oncogenic BRAF occurs in multiple malignancies, making it a potential target in oncology.2 These malignancies include some melanoma tumors, papillary thyroid tumors, serous ovarian tumors, and colorectal tumors:
Knight T, Irving JA. Ras/Raf/MEK/ERK pathway activation in childhood acute lymphoblastic leukemia and its therapeutic targeting. Front Oncol. 2014;4:160. PMID: 25009801
Knight T, Irving JA. Ras/Raf/MEK/ERK pathway activation in childhood acute lymphoblastic leukemia and its therapeutic targeting. Front Oncol. 2014;4:160. PMID: 25009801
Santarpia L, Lippman SL, El-Naggar AK. Targeting the mitogen-activated protein kinase RAS-RAF signaling pathway in cancer therapy. Expert Opin Ther Targets. 2012;16:103-119. PMID: 22239440
Santarpia L, Lippman SL, El-Naggar AK. Targeting the mitogen-activated protein kinase RAS-RAF signaling pathway in cancer therapy. Expert Opin Ther Targets. 2012;16:103-119. PMID: 22239440
Cseh B, Doma E, Baccarini M. “RAF” neighborhood: protein-protein interaction in the Raf/Mek/Erk pathway. FEBS Lett. 2014;588:2398-2406. PMID: 24937142
Cseh B, Doma E, Baccarini M. “RAF” neighborhood: protein-protein interaction in the Raf/Mek/Erk pathway. FEBS Lett. 2014;588:2398-2406. PMID: 24937142
Rauen KA. The RASopathies. Annu Rev Genomics Hum Genet. 2013;14:355-369. PMID: 23875798
Rauen KA. The RASopathies. Annu Rev Genomics Hum Genet. 2013;14:355-369. PMID: 23875798
Chappell WH, Steelman LS, Long JM, et al. Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR inhibitors: rationale and importance to inhibiting these pathways in human health. Oncotarget. 2011;2:135-164. PMID: 21411864
Chappell WH, Steelman LS, Long JM, et al. Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR inhibitors: rationale and importance to inhibiting these pathways in human health. Oncotarget. 2011;2:135-164. PMID: 21411864
Urick ME, Chung EJ, Shield WP III, et al. Enhancement of 5-fluorouracil-induced in vitro and in vivo radiosensitization with MEK inhibition. Clin Cancer Res. 2011;17:5038-5047. PMID: 21690569
Urick ME, Chung EJ, Shield WP III, et al. Enhancement of 5-fluorouracil-induced in vitro and in vivo radiosensitization with MEK inhibition. Clin Cancer Res. 2011;17:5038-5047. PMID: 21690569
Ott PA, Bhardwaj N. Impact of MAPK pathway activation in BRAFV600 melanoma on T cell and dendritic cell function. Front Immunol. 2013;4:346. PMID: 24194739
Ott PA, Bhardwaj N. Impact of MAPK pathway activation in BRAFV600 melanoma on T cell and dendritic cell function. Front Immunol. 2013;4:346. PMID: 24194739
Burrows N, Babur M, Resch J, Williams KJ, Brabant G. Hypoxia-inducible factor in thyroid carcinoma. J Thyroid Res. 2011;2011:762905. PMID: 21765994
Burrows N, Babur M, Resch J, Williams KJ, Brabant G. Hypoxia-inducible factor in thyroid carcinoma. J Thyroid Res. 2011;2011:762905. PMID: 21765994
Cantwell-Dorris ER, O’Leary JJ, Sheils OM. BRAFV600E: implications for carcinogenesis and molecular therapy. Mol Cancer Ther. 2011;10:385-394. PMID: 21388974
Cantwell-Dorris ER, O’Leary JJ, Sheils OM. BRAFV600E: implications for carcinogenesis and molecular therapy. Mol Cancer Ther. 2011;10:385-394. PMID: 21388974
Wang AX, Qi XY. Targeting RAS/RAF/MEK/ERK signaling in metastatic melanoma. IUBMB Life. 2013;65:748-758. PMID: 23893853
Wang AX, Qi XY. Targeting RAS/RAF/MEK/ERK signaling in metastatic melanoma. IUBMB Life. 2013;65:748-758. PMID: 23893853
Ascierto PA, Kirkwood JM, Grob JJ, et al. The role of BRAF V600 mutation in melanoma. J Transl Med. 2012;10:85. PMID: 22554099
Ascierto PA, Kirkwood JM, Grob JJ, et al. The role of BRAF V600 mutation in melanoma. J Transl Med. 2012;10:85. PMID: 22554099
Wangari-Talbot J, Chen S. Genetics of melanoma. Front Genet. 2013;3:330. PMID: 23372575
Wangari-Talbot J, Chen S. Genetics of melanoma. Front Genet. 2013;3:330. PMID: 23372575
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