cancer pathways
TRANSCRIPT
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PATHWAYS to CANCEREman El-AttarMsc, MD, CPHQ
Lecturer of Chemical PathologyMedical Research Institute 2014
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Cellular Signalling Pathway
• Cells receive information from many different growth
factor receptors and from cell-matrix and cell-cell contacts.
• Cellular signaling pathways are not isolated from each
other but are interconnected to form complex signaling
networks
• They must then integrate this information to regulate
diverse processes, such as protein synthesis and cell
growth, motility, cell architecture and polarity,
differentiation, and programmed cell death.
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Cellular Signalling Pathway
• The same signaling molecules are used to control different processes within different signaling complexes or at different intracellular locations.
• Moreover, signaling pathways could generate different outcomes in different cell types.
• The intricacy of cellular signaling networks has major implications on our understanding of tumor cell behavior and our ability to use this knowledge for cancer therapy
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Most Common Signaling Pathways
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But actually the big picture much more complicated, interconnected and looks more like this !!
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Nature Reviews designed the network as a Subway map; stops & lines leading to main stations
Subway map designed by Claudia Bentley.Web design by Nick Allin.Edited by Cath Brooksbank and Sandra Clark.© 2002 Nature Publishing Group.
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Cell Cycle
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Two classes of regulatory proteins:
1) Cyclins: 2) Cyclin Dependant Kinases (CDKs)
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Signalling pathways
• Mutations in components of signaling pathways that control cell growth underlie tumour initiation
• Ras, PI(3)K and mTOR are 3 signaling pathways that form an intersecting biochemical network. When mutated, these drive unrestricted cell growth.
• Ultimately, these pathways drive tumorigenesis through the coordinated phosphorylation of proteins that directly regulate protein synthesis, cell-cycle progression and metabolism, and of transcription factors that regulate expression of genes involved in these processes
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The Ras pathway
• The name 'Ras' is an abbreviation of 'Rat sarcoma'
• RAS is a family of GTPases that are activated by a wide range of cell-surface molecules
• 3 isoforms : KRAS, NRAS, HRAS
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The Ras pathway
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Evading apoptosis Proliferation
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The importance of this pathway is that multiple signals are funneled into MEK and ERK kinases (this pathway), allowing a nodal point for therapeutic targeting.It is is like a bottle neck where therapy can be targetted
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The Ras/RAF/MAP kinase pathway
• Upstream components of the pathway, such as the RAS and RAF are potent oncogenes. In cooperation with other events, can lead to profound changes , transforming normal cells into fully malignant .
• Components of this pathway are under intense investigation as possible targets for anti-cancer therapeutics.
• Mutated Ras is associated with 20−30% of all human ∼cancers are often not responsive to established therapies
• Resulting in a staggering 3 million new cancers diagnosed worldwide each year with RAS mutations.
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RAS mutations
• In particular, K-Ras, the most frequently mutated Ras isoform, is considered one of the most important but 'undruggable' targets in cancer research.
• Despite intense efforts in pharmaceutical industry and academia, a therapeutic grip on oncogenic Ras proteins has remained elusive.
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RAS mutations• Described in both hematologic and solid-tumor malignancies.• Different cancers (based on cell type of origin) show a propensity
to mutate different RAS isoforms. – KRAS is the dominantly mutated isoform in colorectal and lung cancers– NRAS mutations dominate in hematologic malignancies and melanoma
• Cancers with the most frequent RAS mutations are pancreatic cancer (90%), colorectal cancer (40%), non–small cell lung cancer (30%), bladder cancer (30%), peritoneal cancer (30%), cholangiocarcinoma (25%), and melanoma (15%).
• In contrast, lymphomas, acute lymphoblastic leukemia, hepatocellular carcinoma, osteosarcoma, and prostate cancer less commonly contain RAS mutations.
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RAF mutations
• RAF kinases have 3 isoforms: BRAF, CRAF, ARAF
• Identifying mutations in BRAF in human cancer has opened up profound new therapeutic opportunities for the management of cancer.
• 6% of human cancers contain activating mutations in BRAF that result in more than 500,000 new cases of BRAF-mutated cancer diagnosed worldwide each year.
• Similar to RAS mutations, BRAF mutations are profoundly oncogenic in cooperation with other genetic events and are capable of fully transforming normal cells.
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BRAF mutations• The most common mutation in BRAF by far is the substitution of
valine 600 by glutamic acid (V600E), which accounts for– more than 85% of the BRAF mutations in melanoma,
– more than 50% of the mutations in non-small cell lung cancer
– more than 95% of mutations in colorectal cancer, cholangiocarcinoma, and hairy-cell leukemia.
• Just as RAS-mutated cells, BRAF mutation, are dependent on MEK and, by inference, ERK signaling for cell survival and proliferation.
• MEK inhibitor: trametinib or dacarbazine (downstream)
• BRAF inhibitors: vemurafenib, dabrafenib (upstream)
• LGX818 F
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PI3K/AKT/mTOR pathway
• The PI3K/AKT/MTOR pathway is an intracellular signalling pathway important in apoptosis and hence cancer(e.g. breast cancer and non-small-cell lung cancer) and longevity.
• The PI3K/AKT/MTOR pathway is activated by IGF1 and has a number of downstream effects which either promote protein synthesis or inhibit protein breakdown.
• In many cancers, this pathway is overactive, thus reducing apoptosis and allowing proliferation.
• Cancer drugs trials aim to inhibit this signalling sequence at some point.
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Combination of PI3K and MEK inhibitory drugs (in purple) to block the growth of lung tumors in a RAS-driven mouse transgenic mode Nature Medicine 14, 1315 - 1316 (2008)
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mTOR
• Mammalian Target of Rapamycin• Two distinct and mutually exclusive TOR complexes:– Raptor (the mTORC1 complex) : strongly inhibited by
rapamycin (main focus of research)– Rictor (mTORC2)
• Growth factors signal to mTORC1 complexes through both PI3(K)-AKT & Ras-ERK pathway.
• Low nutrient availability (for example, low glucose or hypoxia) inhibits mTORC1
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PI3K/AKT/mTOR pathway
PI3 K
: mutationally activated in cancer
: mutationally inhibited in cancer
Red
Green
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: mutationally activated in cancer
: mutationally inhibited in cancer
Cell growth, Gycolysis and Angiogenesis
Red
Green
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• These findings have strong implications for cancer therapeutic strategies.
• Rapamycin-based mTOR inhibitors• Inhibitors of PI(3)K–AKT signaling• Prolonged use of an inhibitor of a certain
pathway (e.g. Rapamycin) could lead to enhanced activation of another pathway (PI3K). Thus combinations of drugs may be useful to avoid bypass routes
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THANK YOUEman