20.06.09 Cancer pathways Flashcards
List main cancer pathways
- MAPK (ERK, JNK, P38, ERK5 pathways)
- WNT
- PI3K/AKT
- TGFβ
- Although due to complex cross talk between pathways, they cannot be considered in isolation
Review of MAPK pathway
- MAPK (Mitogen-activated protein kinase)
- Links extracellular signals to fundamental cellular processes (proliferation, differentiation, migration, apoptosis)
- 4 MAPK pathways. ERK, JNK, P38, ERK5
Review of ERK pathway
- Extracellular signal-regulated kinase (ERK) MAPK pathway.
- Deregulated in 30% of cancers.
- Raf phosphorylates MEK, which phosphorylates ERK.
- ERK activation promotes upregulated expression of EGFR ligands (TGFα)
- Creates an positive feedback loop which is critical for tumourigenesis
Common mutations in EGFR/Ras/Raf/ MEK/ ERK pathway
- EGFR: exon 19 mutations account for 90% of non-small cell lung cancer.
- RAS (HRAS, KRAS, NRAS): most commonly mutated oncogenes in human cancer. Lead to constitutively active proteins.
- RAF (BRAF). V600E most common (90%)
Drug therapies targeting EGFR/Ras/Raf/ MEK/ ERK pathway
- RAF inhibitor= vemurafenib and MEK inhibitor= trametinib, used for BRAF mut malignant melanoma.
- KRAS-wt= Cetuximab for colorectal cancer
- EGFR- mut= Gefitinib.
What are the stress activated MAPK pathways
- JNK family of kinases respond to cytokines, UV radiation, DNA damage reagents. Activates c-Jun and phosphorylates p53 (leading to apoptosis)
- p38 MAPK are activated by environmental stress and activates p53 (apoptosis).
What are WNTs
- A Family of 19 secreted glycoproteins
- Involved in the regulation of cellular process such as self-renewal, proliferation, differentiation, survival, migration
What are the two WNT pathways
- CTNNB1 dependent (canonical)
- CTNNB1 independent (non-canonical)
Review of canonical WNT signalling
- Activated by the binding of a Wnt-protein ligand to a Frizzled family receptor, which passes the biological signal to the Dishevelled protein inside the cell.
- causes an accumulation of β-catenin in the cytoplasm and its eventual translocation into the nucleus to act as a transcriptional coactivator of transcription factors that belong to the TCF/LEF family.
- In the absence of WNT, a destruction complex containing APC, GSK3B and AXIN1 target CTNNB1 for ubiquitylation and thus proteosomal degradation.
Examples of somatic mutations in WNT pathways
- APC: seen in 39% of cancers of large intestine
- CTNNB1: seen in 42% soft tissue cancers.
- AXIN1: seen in 38% biliary tract cancers.
Effect of somatic mutations on WNT pathway
-Inactivate APC, AXIN1 or WTX, leading to hyperactivation of signalling pathway (accumulation of β-catenin).
Example of cross communication between WNT and EGFR/Ras/Raf/Mek/ERK pathways
- β-catenin can bind to EGFR
- EGFR can activate β-catenin-dependent signalling through PI3K
Therapies targeting WNT pathway
- Direct targeting of WNT signalling has been difficult due to lack of pathway-specific targets and redundancy of many pathway components.
- Examples: small molecules, blocking antibodies, peptides
- Combination therapies, where inhibiting canonical WNT pathway sensitizes cells to chemotherapeutics.
What is the PI3K/AKT pathway
-Downstream of a receptor tyrosine kinase and G-protein coupled receptors, leading to activation of serine/threonine kinase AKT and down stream effector pathways.
Key components of PI3K/AKT pathway
- PI3K (phosphatidyl 3-kinases), lipid kinase heterodimer composed of a regulatory and catalytic subunit. PIK3CA gene encodes the catalytic subunit.
- AKT1, serine/threonine kinases that acts downstream of PI3K.
- PTEN. Negative regulator of PI3K pathway (often downregulated in cancer)
- mTOR (mammalian target of rapamycin), serine/threonine kinase that is involved in regulating cell growth and proliferation by monitoring nutrient availability and cellular energy levels. Influenced by activity of TCS2/1 complex
Review of PI3K/AKT pathway in cancer
- Aberrant signalling affects cell proliferation, survival, motility and angiogenesis.
- Somatic PIK3CA mutations are seen in 32% of CRC
- Inactivating somatic PTEN mutations in many cancer types. Can be identified via immunohistochemistry.
- Activating somatic mutations in AKT1 in 1-6% CRCs and other cancer types.
- Often mutations are mutually exclusive (i.e. AKT1 and PTEN or AKT1 and PI3K are mutually exclusive)
- Activating mTOR mutations lead to hyperactivation of downstream pro-survival signalling pathways.
Examples of cancer therapies that target PI3K/AKT pathway
- PI3K inhibitors (pan-PI3K or isoform specific).
- PTEN loss makes colorectal cancers less sensitive to anti-EGFR antibodies, so patients would not benefit from cetuximab.
- mTOR inhibitors.
- SAR24509 and BEZ235 are dual PI3KmTOR inhibitors
Other disease pathologies caused by PI3K/AKT pathway
- Diabetes, heart conditions, hamartoma syndromes.
- e.g. PTEN hamartoma tumour syndrome
What is the TGFβ pathway
- Regulates differentiation, migration and cell death during normal development.
- Operates through two tyrosine kinase receptors TβRI and TβRII
What two receptors are involved in the TGFβ pathway
- TβRII is constitutively active
- TβRI is activated after ligand binding
What happens in TGFβ pathway
- Binding of TGFβ to receptor leads to release of inhibitory FKBP12.
- Activated TβRI receptor phosphorylates and activates SMAD2 and SMAD3 (R-SMADs), which in turn binds SMAD4 to form SMAD4/R-SMAD complex.
- SMAD4/R-SMAD complex translocates to the nucleus to activate gene expression.
What happens in non-canonical TGFβ signalling
-Activates MAPK pathway, PI3K/AKT pathway and Rho-like GTPase signalling pathways.
What are the components of TGFβ pathway
- TGFβ: 30 different members. TGFβ , activins, BMPs (bone morphogenetic proteins), GDFs (growth and differentiation factors), AMH (anti-Müllerian hormone)
- SMAD4: one of 8 SMAD proteins. Signal transduction protein that is a central mediator for downstream signalling pathways.
Involvement of TGFβ pathway in cancer
- High TGFβ levels correlate with increased angiogenesis
- 35% of metastatic CRCs have mutations in components of TGFβ pathway
- SMAD4 loss is seen in 50% of pancreatic mutations. Reduced SMAD4 protein expression on immunohistochemistry is associated with worse overall survival.
- Inactivating SMAD2 mutations seen in 6% of CRCs.
