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Cancer Pathways

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Cellular Signaling Pathways have direct implications on our understanding of tumor cell behavior. A general overview is presented here followed by a brief discussion of some of the major pathways currently implicated in cancer progression : Ras/RAF/MAP kinase pathway and PI3K/AKT/mTOR pathways

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Cancer Pathways

  1. 1. 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.
  2. 2. 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
  3. 3. Most Common Signaling Pathways
  4. 4. But actually the big picture much more complicated, interconnected and looks more like this !!
  5. 5. Nature Reviews designed the network as a Subway map; stops & lines leading to main stations Subway map designed by Claudia Bentley. Web
  6. 6. Cell Cycle
  7. 7. Two classes of regulatory proteins: 1) Cyclins: 2) Cyclin Dependant Kinases (CDKs)
  8. 8. 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
  9. 9. 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
  10. 10. The Ras pathway
  11. 11. Evading apoptosis Proliferation
  12. 12. 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
  13. 13. 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.
  14. 14. 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.
  15. 15. 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.
  16. 16. 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.
  17. 17. 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
  18. 18. 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.
  19. 19. 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)
  20. 20. 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
  21. 21. PI3K/AKT/mTOR pathway PI3 K : mutationally Red activated in cancer : mutationally Green inhibited in cancer
  22. 22. : mutationally activated in cancer : mutationally inhibited in cancer Cell growth, Gycolysis and Angiogenesis Red Green
  23. 23. • 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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