Cancer (1) Molecular Mechanisms of Cancer Flashcards
Cancer
Disease caused by uncontrolled division of abnormal cells in a part of the body
Or rather - a collection of diseases
Cancer is the 2nd leading cause of death in most developed countries (after cardiovascular disease)
**colorectal cancer generally classified as 1 type, not 2
How does cancer develop?
Initial genetic alteration may be
>spontaneous/stochastic/heriditary
>or environmentally induced
Carcinogenesis is a multi-step process
E.g. Sequential alterations in colorectal cancer pathogenesis
> Initiation (first “hit”)
>environmental trigger (sporadic)
>spontaneous/stochastic mutations
>germinal mutation (hereditary)
>Progression >>second "hit" >>proto-oncogene mutations >>accumulation of more mutations >>metastasis
Altered growth
Erratic growth
>slow or rapid, mitotic figures may be numerous and abnormal
Growth rate of tumours reflects combined influences of
>doubling time of tumour cells
>proportion of tumour cells actually dividing
>Death rate of tumour cells
Selective growth advantage of tumour cells vs healthy counterpart is small
Non-selective targeting of cell division
Proliferative pool (sensitive to chemotherapy) vs nonproliferative pool (insensitive to chemotherapy)
Nature of gene alterations in cancer
Genetic alterations can come in different flavours
Gene mutations
>point mutations/altered sequence
>frameshift/stop codon mutations/shorter protein
Insertions/Deletions (indels)
Gene amplification
Gene translocation/fusion
>(e.g. BCR/ABL in CML, coming from 22q11/9q34 fusion)
Molecular basis of cancer
Inappropriate activation of proto-oncogenes
Inactivation of Tumour suppressor genes
> Driving mutations or other genetic alterations usuually affects several of these pathways
Oncogene activation
Induction of self-sufficient growth
Proto-oncogenes
>normal cellular genes encoding proteins mostly involved in
>promoting proliferation or
>suppressing differentiation/apoptosis
Oncogenes:
>genetically altered (often mutated) version
>active in unregulated manner
>independently from growth-promoting signals
Main classes of oncogenes
(overexpression, permanent/constitutive activation)
>growth factors
>growth factor receptors
>signal transduction proteins e.g. protein kinases, GTPases
>transcription factors
>cyclins and cyclin-dependent kinases (cell cycle control)
Oncogene activation
Proteins involved in signal transduction
GTP-binding
KRAS > point mutation > colon, lung and pancreatic tumours
HRAS > point mutation > bladder and kidney tumors
NRAS > point mutation > melanomas, hematologic malignancies
Oncogene activation
Growth factor receptors
EGF-receptor family
> ERBB1 (EGFR), ERRB2 > overexpression > squamous cell carcinoma of lung, gliomas
Oncogene activation
the example of RAS
Upon RAS mutation
> RAS/MAP kinase pathway becomes permanently activated
no more requirement for activating signals from growth factors
Oncogene activation
RAS targeting approaches
Salirasib
>blocks membrane association of RAS
>cleaves Famesyl membrane anchor
>shut down signalling
MRTX849 (Mirati Therapeutics)
>covalently binds to codon 12 cysteine in G12C mutant
AZD4785 (Astra Zeneca)
>antisense oligonucleotide targeting of KRAS mRNA
>stop production of new RAS, at some point there will be no more RAS
+ multiple inhibitors targeting downstream targets
Where is the best target in any given cancer-driving pathway?
E.g. Alteration of KIT/RAS/MAP kinase pathway in Melanoma
Essentially many targets downstream, and targeting one step in the pathway sometimes causes cancer cell to develop other mutations in response to that selective pressure
What about receptors and their ligands?
HER family of trans-membrane receptors
(Receptor tyrosine kinase)
(HER = human epidermal growth factor receptors)
EGFR/HER1
>one of the key growth factor receptors in most tissues
HER2 does not bind to any ligand
>reacts to binding of other ligands on other receptors
>can get heterodimerisation of HER1/HER2, or HER2/HER4 etc and activate the HER2 pathway as well
HER3 and HER 4
All result in dimerisation
>result in activation of PI3K pathway and Ras/Ref/MEK/MAPK pathways
> > key in proliferation, motility, invasiveness, resistance to apoptosis, angiogenesis
You can have mutations at receptor level instead of mutations downstream
HER2 amplification
>20% of breast cancers
EGFR amplification
>10% of colorectal cancers (but can have further mutations downstream in KRAS or BRAF)
>10% NSCLC
(non-small-cell lung carcinoma)
EGFR activating mutations
>10% NSCLC
Anti-HER targeted approaches
HER2 dimerisation inhibitors
>Trastuzumab
>block dimerisation of HER2 to any of the other receptors
>block downstream signalling pathway of HER2
Anti EGFR blocking antibodies
>Cetuximab
>colorectal cancer patients who dont have a mutation downstream
>Antibody binds in receptor active sites, blocks ligand binding
Anti-ligand blocking antibodies
>block ligand
>e.g. Anti-VEGF
Tyrosine kinase inhibitors
>Erlotinib, Gefitinib, Iapatinib
>bind to ATP pockets and block activity of the receptor
Ligand-toxin conjugates
>binds to receptor, toxin comes so close to cell that it kills the cell
>risky - need very high amplification of receptors or else risk binding to normal cells
Tumour suppression inactivation
Loss of sensitivity to growth inhibition and senescence-inducing signals
APC/Beta-catenin gene in cytosol
>Functions as inhibition of signal transduction
>Somatic mutations associated with carcinomas of stomach, colon, pancreas, melanomas
>Inherited mutations associated with familial adenomatous polyposis coli/colon cancer
Mostly (but not always) follow the “two-hit” model
(i.e. both alleles must be inactivated for full impact)
>one normal is enough to keep it in check
Tumour suppressor genes - Two major categories
Gatekeepers
>regulate apoptotic pathways (p53, Rb1)
>regulate proliferation (APC)
Caretakers
>BRCA1 (rarely mutated in breast cancers but often methylation), BRCA2, MSH2, MLH1
>involved in DNA repair
>when damage occurs, DNA repair in a correct manner, or else cell will go through cell death
>when dysfunctional, cell does not go through DNA repair
Tumour suppressor inactivation
Example of APC
APC gene regulator of Wnt signalling pathway
>controls destruction of beta-catenin (protein that moves into nucleus and is involved in adhesion and transcriptional regulation)
> Destruction complex is inhibited by Wnt-induced signals in normal cells
> When APC loss of function, destruction complex is constitutively inactivated
>constant beta-catenin flooding nucleus and promoting transcription of many proteins involved in proliferation
Epigenetics
Inherited changes in phenotype or gene expression
>caused by mechanisms other than chances in underlying DNA sequence
> > modifying structure of chromatin
Cancer epigenetics
3 main components of the epigenetic code
>DNA methylation
>Histone modification
>small non-coding RNAs (e.g. miRNAs) that modulate gene expression
Enzymes that apply histone modifications
>called writing enzymes
Enzymes that remove histone modifications
>called erasing enzymes
Enzymes that can bind to DNA once modifications are present
>called reading enzymes
A key role for the tumor microenvironment
Targeting the microenvironment so that we can stop tumor growth
> avoiding immune destruction
Inducing angiogenesis
Impact of the microenvironment on tumour cells
>other cells, signalling molecules, cell-cell contacts, cell-matrix contacts, biophysical forces
Microenvironment support multiple stages of tumour devleopment, opening the door for multiple targeting avenues
Tumour vasculature
Immune activation*
Altered immune cell recruitment, expansion and depletion
Repolarisation and re-education
Metastasis and/or outgrowth
Oncology meets immunology: the cancer-immunity cycle
Early tumour cells normally killed off by immune system
sometimes, tumour cells get past this and escape immune system killing
