The MAPK pathway, revisited

The MAPK pathway, revisited

The mitogen-activated protein kinase (MAPK) signalling pathway plays a key role in the regulation of gene expression, cellular growth, and survival.1,2 Abnormal MAPK signalling 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, Roche is investigating further ways to target MAPK signalling.

The MAPK pathway includes the signalling molecules Ras, Raf, MEK, and ERK. In normal cells, extracellular growth factors bind to and activate receptor tyrosine kinases, causing a downstream signalling cascade. This process leads to the transcription of genes that encode proteins. These proteins regulate essential cellular functions, such as cell growth, cell proliferation, and cell differentiation.1,3

The MAPK pathway, revisited

The MAPK signalling cascade – Ras, Raf, MEK, and ERK1

First

MAPK signalling 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, another key 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 that regulate cell proliferation and survival.2,4

What happens when MAPK signalling goes awry?

Dysregulated MAPK signalling is implicated in a wide range of cancers and occurs via multiple mechanisms, including abnormal expression or activating mutations in receptors and activating mutations in genes, including BRAF.2,5

Abnormal MAPK signalling may lead to5-8

Increased or uncontrolled cell proliferation
Increased or uncontrolled cell proliferation
Resistance to apoptosis (programmed cell death)
Resistance to apoptosis (programmed cell death)
Resistance to chemotherapy, radiotherapy, and targeted therapies
Resistance to chemotherapy, radiotherapy, and targeted therapies
Mutated BRAF can lead to abnormal MAPK signalling

Mutated BRAF can lead to abnormal MAPK signalling9

Mutations in the BRAF gene can cause a key protein in the MAPK signalling pathway, BRAF, to become oncogenic.9

Mutated BRAF signals independently of upstream cues, leading to overactive downstream signalling via MEK and ERK.9,10 This dysregulated signalling results in excessive cell proliferation and survival, independent of growth factors, and may play a role in specific malignancies.2,10

Approximately 90% of known BRAF mutations are V600E mutations.9

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 signalling is implicated in a number of tumour types2

Overactivation of MAPK signalling by oncogenic BRAF occurs in multiple malignancies, making it a potential therapeutic target in oncology.2 These malignancies include some melanoma tumours, papillary thyroid tumours, serous ovarian tumours, and colorectal tumours:

The MAPK pathway plays an important role in metastatic melanoma

The MAPK pathway plays an important role in metastatic melanoma10

The dysregulation of BRAF signalling in the MAPK pathway has been shown to be one of the key drivers of metastatic melanoma.10

Oncogenic BRAF mutations have been reported at various stages of melanoma, suggesting their role in disease progression along the clinical course, which includes initiation, malignant transformation, tumour progression, and metastasis.11,12 Approximately 50% of melanomas harbour BRAF mutations at position V600, the majority of which are BRAF V600E mutations.11

Since the discovery of BRAF V600E mutations in melanoma in 2002, scientists and clinicians have learned much about the role of mutated BRAF V600E, but many questions remain unanswered, and research is ongoing.13

The rapidly increasing incidence of melanoma, coupled with its highly aggressive metastatic nature, make this an active and exciting area of research.7,10,12

Is there more we can do to target the MAPK pathway?

Is there more we can do to target the MAPK pathway?

The inhibition of MAPK signalling has the potential to inhibit growth in a variety of tumour types.

Because mutated BRAF is prevalent in different types of cancer, including melanoma, it is a potential therapeutic target.2 Inhibiting oncogenic BRAF activity may result in decreased tumour cell proliferation and increased tumour cell death. The inhibition of MEK may also help overcome activated BRAF, which is further upstream from MEK in the MAPK cascade.10,11

Based on these findings, Roche is investigating further ways to target MAPK signalling.

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.
  • 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.
  • 3. Cseh B, Doma E, Baccarini M. “RAF” neighborhood: protein-protein interaction in the Raf/Mek/Erk pathway. FEBS Lett. 2014;588:2398-2406.
  • 4. Rauen KA. The RASopathies. Annu Rev Genomics Hum Genet. 2013;14:355-369.
  • 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.
  • 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.
  • 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.
  • 8. Burrows N, Babur M, Resch J, et al. Hypoxia-inducible factor in thyroid carcinoma. J Thyroid Res. 2011;2011:762905.
  • 9. Cantwell-Dorris ER, O’Leary JJ, Sheils OM. BRAFV600E: implications for carcinogenesis and molecular therapy. Mol Cancer Ther. 2011;10:385-394.
  • 10. Wang AX, Qi XY. Targeting RAS/RAF/MEK/ERK signaling in metastatic melanoma. IUBMB Life. 2013;65:748-758.
  • 11. Ascierto PA, Kirkwood JM, Grob JJ, et al. The role of BRAF V600 mutation in melanoma. J Transl Med. 2012;10:85.
  • 12. Wangari-Talbot J, Chen S. Genetics of melanoma. Front Genet. 2013;3:330.
  • 13. Fedorenko IV, Paraiso KH, Smalley KS. Acquired and intrinsic BRAF inhibitor resistance in BRAF V600E mutant melanoma. Biochem Pharmacol. 2011;82:201-209.

Glossary

  • Apoptosis A type of cell death in which a series of molecular steps in a cell leads to its death. This is the body's normal way of getting rid of unneeded or abnormal cells. The process of apoptosis may be blocked in cancer cells. Also called programmed cell death.
    National Cancer Institute. Dictionary of Cancer Terms.
    http://www.cancer.gov/dictionary. Accessed July 28, 2014.
  • BRAF BRAF is a member of the Raf family of serine/threonine kinases and is an integral part of the Ras-Raf pathway.
  • ERK Extracellular signal-regulated kinase (ERK) is a protein kinase that is a part of the Ras-Raf pathway. ERK is a type of MAPK. Activation of ERK results in the activation of transcription factors that lead to the expression of genes. These genes regulate cell proliferation and survival.
  • MAPK Mitogen-activated protein kinases (MAPKs) are enzymes with serine/threonine kinase activity (eg, ERK). MAPKs regulate various cellular processes, such as cell proliferation and cell differentiation, via downstream cellular regulatory targets in response to extracellular stimuli.
  • MEK MEK is a protein kinase that is a part of the Ras-Raf signalling cascade that regulates expression of a large number of proteins involved in the control of cell proliferation, differentiation, and apoptosis.
  • Raf Raf is a protein kinase family implicated in cellular responses relevant to tumourigenesis, including cell proliferation, invasion, survival, and angiogenesis. The Raf family comprises 3 members—ARAF, BRAF, and CRAF—each of which has a different function and is differentially regulated at various levels.
  • Ras Ras is a GTP-binding protein that is activated in response to the binding of growth factors, cytokines, and hormones to cell-surface receptors. The GTP-bound forms of Ras directly bind and recruit Raf to the plasma membrane.
  • Receptor tyrosine kinases (RTKs) Receptor tyrosine kinases are membrane-spanning, cell-surface proteins that contain an N-terminal extracellular ligand binding domain and a C-terminal intracellular tyrosine kinase domain.
    McKay MM, Morrison DK. Integrating signals from RTKs to ERK/MAPK. Oncogene. 2007;26:3113-3121.

October 2014, PR/COBI/1410/0002