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Understanding the MAPK pathway as it relates to 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, Genentech is investigating further ways to impact MAPK signaling.

The MAPK signaling pathway plays a role in the regulation of gene expression, cellular growth, and survival2

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

Oncogenic signaling in the MAPK pathway image

The MAPK signaling cascade—Ras, Raf, MEK, and ERK1

The MAPK signaling cascade: Ras, Raf, MEK, and ERK image

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

What happens when MAPK signaling goes awry?

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

Abnormal MAPK signaling may lead to5-8

 

Increased or uncontrolled cell proliferation image

Increased or uncontrolled cell proliferation

Resistance to apoptosis (programmed cell death) image

Resistance to apoptosis (programmed cell death)

Pharmacy, therapy, treatment image

Resistance to chemotherapy, radiotherapy, and targeted therapies

Mutated BRAF can lead to abnormal MAPK signaling9

Mutations in the BRAF gene lead to the formation of an oncogenic Raf molecule, known as BRAF or B Raf, in the MAPK signaling pathway9

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

Mutated BRAF image

Approximately 90% of known BRAF mutations are V600E mutations9

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

Dysregulated MAPK signaling is implicated in a number of tumor types2

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:

 

Dysregulated MAPK signaling rates by tumor type image

Based on these findings, Genentech is investigating further ways to target MAPK signaling

References

  1. 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
  2. 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 
  3. 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
  4. Rauen KA. The RASopathies. Annu Rev Genomics Hum Genet. 2013;14:355-369. PMID: 23875798
  5. 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
  6. 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
  7. 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
  8. Burrows N, Babur M, Resch J, Williams KJ, Brabant G. Hypoxia-inducible factor in thyroid carcinoma. J Thyroid Res. 2011;2011:762905. PMID: 21765994
  9. Cantwell-Dorris ER, O’Leary JJ, Sheils OM. BRAFV600E: implications for carcinogenesis and molecular therapy. Mol Cancer Ther. 2011;10:385-394. PMID: 21388974
  10. Wang AX, Qi XY. Targeting RAS/RAF/MEK/ERK signaling in metastatic melanoma. IUBMB Life. 2013;65:748-758. PMID: 23893853
  11. Ascierto PA, Kirkwood JM, Grob JJ, et al. The role of BRAF V600 mutation in melanoma. J Transl Med. 2012;10:85. PMID: 22554099
  12. Wangari-Talbot J, Chen S. Genetics of melanoma. Front Genet. 2013;3:330. PMID: 23372575

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