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Cell Signaling in Cancer

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Molecular and Cell Biology of Cancer

Part of the book series: Learning Materials in Biosciences ((LMB))

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Abstract

In this chapter we will explain what cell signaling is, how it works, what it serves for and especially why it is important in the context of cancer. The basics about three key signaling pathways, JAK/STAT, MEK/ERK and PI3K/Akt/mTOR, which are frequently involved in all different types of cancer will be adressed. Many other signaling pathways exist, such as Notch, Wnt, Hedgehog, etc., that also partake in tumorigenesis. We will also address what consist the so-called “signaling therapies”, which are their advantages, understand their potential and have some insight into the mechanisms that explain why they frequently fail. We will tackle some of the strategies aiming at overcoming resistance associated with signaling therapies and their possible caveats. Finally, we hope it will be clear the need for a deep characterization of the cancer patient in order to devise the best targeted therapies.

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References

  1. Pawson T, Nash P (2000) Protein-protein interactions define specificity in signal transduction. Genes Dev 14:1027–1047

    CAS  PubMed  Google Scholar 

  2. Yarden Y, Sliwkowski MX (2001) Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2:127–137. https://doi.org/10.1038/35052073

    Article  CAS  PubMed  Google Scholar 

  3. Adjei AA, Hidalgo M (2005) Intracellular signal transduction pathway proteins as targets for cancer therapy. J Clin Oncol 23:5386–5403. https://doi.org/10.1200/JCO.2005.23.648

    Article  CAS  PubMed  Google Scholar 

  4. Blume-Jensen P, Hunter T (2001) Oncogenic kinase signalling. Nature 411:355–365. https://doi.org/10.1038/35077225

    Article  CAS  PubMed  Google Scholar 

  5. Goldstein BJ (1992) Protein-tyrosine phosphatases and the regulation of insulin action. J Cell Biochem 48:33–42. https://doi.org/10.1002/jcb.240480107

    Article  CAS  PubMed  Google Scholar 

  6. Luo J, Solimini NL, Elledge SJ (2009) Principles of cancer therapy: oncogene and non-oncogene addiction. Cell 136:823–837. https://doi.org/10.1016/j.cell.2009.02.024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Hopkins AL, Groom CR (2002) The druggable genome. Nat Rev Drug Discov 1:727–730. https://doi.org/10.1038/nrd892

    Article  CAS  PubMed  Google Scholar 

  8. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674. https://doi.org/10.1016/j.cell.2011.02.013

    Article  CAS  PubMed  Google Scholar 

  9. Rane SG, Reddy EP (2000) Janus kinases: components of multiple signaling pathways. Oncogene 19:5662–5679. https://doi.org/10.1038/sj.onc.1203925

    Article  CAS  PubMed  Google Scholar 

  10. O’Shea JJ et al (2015) The JAK-STAT pathway: impact on human disease and therapeutic intervention. Annu Rev Med 66:311–328. https://doi.org/10.1146/annurev-med-051113-024537

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Leonard WJ, O’Shea JJ (1998) Jaks and STATs: biological implications. Annu Rev Immunol 16:293–322. https://doi.org/10.1146/annurev.immunol.16.1.293

    Article  CAS  PubMed  Google Scholar 

  12. Bowman T, Garcia R, Turkson J, Jove R (2000) STATs in oncogenesis. Oncogene 19:2474–2488. https://doi.org/10.1038/sj.onc.1203527

    Article  CAS  PubMed  Google Scholar 

  13. Lord JD, McIntosh BC, Greenberg PD, Nelson BH (2000) The IL-2 receptor promotes lymphocyte proliferation and induction of the c-myc, bcl-2, and bcl-x genes through the trans-activation domain of Stat5. J Immunol 164:2533–2541

    Article  CAS  PubMed  Google Scholar 

  14. Roux PP, Blenis J (2004) ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions. Microbiol Mol Biol Rev 68:320–344. https://doi.org/10.1128/MMBR.68.2.320-344.2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Dhillon AS, Hagan S, Rath O, Kolch W (2007) MAP kinase signalling pathways in cancer. Oncogene 26:3279–3290. https://doi.org/10.1038/sj.onc.1210421

    Article  CAS  PubMed  Google Scholar 

  16. Smith JA, Poteet-Smith CE, Malarkey K, Sturgill TW (1999) Identification of an extracellular signal-regulated kinase (ERK) docking site in ribosomal S6 kinase, a sequence critical for activation by ERK in vivo. J Biol Chem 274:2893–2898

    Article  CAS  PubMed  Google Scholar 

  17. Waskiewicz AJ, Flynn A, Proud CG, Cooper JA (1997) Mitogen-activated protein kinases activate the serine/threonine kinases Mnk1 and Mnk2. EMBO J 16:1909–1920. https://doi.org/10.1093/emboj/16.8.1909

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Deak M, Clifton AD, Lucocq LM, Alessi DR (1998) Mitogen- and stress-activated protein kinase-1 (MSK1) is directly activated by MAPK and SAPK2/p38, and may mediate activation of CREB. EMBO J 17:4426–4441. https://doi.org/10.1093/emboj/17.15.4426

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Davis RJ (1995) Transcriptional regulation by MAP kinases. Mol Reprod Dev 42:459–467. https://doi.org/10.1002/mrd.1080420414

    Article  CAS  PubMed  Google Scholar 

  20. Kerkhoff E, Rapp UR (1998) Cell cycle targets of Ras/Raf signalling. Oncogene 17:1457–1462. https://doi.org/10.1038/sj.onc.1202185

    Article  CAS  PubMed  Google Scholar 

  21. Barata JT, Cardoso AA, Boussiotis VA (2005) Interleukin-7 in T-cell acute lymphoblastic leukemia: an extrinsic factor supporting leukemogenesis? Leuk Lymphoma 46:483–495. https://doi.org/10.1080/10428190400027852

    Article  CAS  PubMed  Google Scholar 

  22. Song G, Ouyang G, Bao S (2005) The activation of Akt/PKB signaling pathway and cell survival. J Cell Mol Med 9:59–71

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Cantley LC (2002) The phosphoinositide 3-kinase pathway. Science 296:1655–1657. https://doi.org/10.1126/science.296.5573.1655

    Article  CAS  PubMed  Google Scholar 

  24. Laplante M, Sabatini DM (2012) mTOR signaling in growth control and disease. Cell 149:274–293. https://doi.org/10.1016/j.cell.2012.03.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Vander Haar E, Lee SI, Bandhakavi S, Griffin TJ, Kim DH (2007) Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat Cell Biol 9:316–323. https://doi.org/10.1038/ncb1547

    Article  CAS  PubMed  Google Scholar 

  26. Shaw RJ, Cantley LCR (2006) PI(3)K and mTOR signalling controls tumour cell growth. Nature 441:424–430. https://doi.org/10.1038/nature04869

    Article  CAS  PubMed  Google Scholar 

  27. Richter JD, Sonenberg N (2005) Regulation of cap-dependent translation by eIF4E inhibitory proteins. Nature 433:477–480. https://doi.org/10.1038/nature03205

    Article  CAS  PubMed  Google Scholar 

  28. Ma XM, Blenis J (2009) Molecular mechanisms of mTOR-mediated translational control. Nat Rev Mol Cell Biol 10:307–318. https://doi.org/10.1038/nrm2672

    Article  CAS  PubMed  Google Scholar 

  29. Roskoski R Jr (2004) The ErbB/HER receptor protein-tyrosine kinases and cancer. Biochem Biophys Res Commun 319:1–11. https://doi.org/10.1016/j.bbrc.2004.04.150

    Article  CAS  PubMed  Google Scholar 

  30. Rowinsky EK (2004) The erbB family: targets for therapeutic development against cancer and therapeutic strategies using monoclonal antibodies and tyrosine kinase inhibitors. Annu Rev Med 55:433–457. https://doi.org/10.1146/annurev.med.55.091902.104433

    Article  CAS  PubMed  Google Scholar 

  31. Van Cutsem E et al (2009) Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 360:1408–1417. https://doi.org/10.1056/NEJMoa0805019

    Article  PubMed  Google Scholar 

  32. Engelman JA (2009) Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 9:550–562. https://doi.org/10.1038/nrc2664

    Article  CAS  PubMed  Google Scholar 

  33. Flex E et al (2008) Somatically acquired JAK1 mutations in adult acute lymphoblastic leukemia. J Exp Med 205:751–758. https://doi.org/10.1084/jem.20072182

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Furqan M, Mukhi N, Lee B, Liu D (2013) Dysregulation of JAK-STAT pathway in hematological malignancies and JAK inhibitors for clinical application. Biomark Res 1:5. https://doi.org/10.1186/2050-7771-1-5

    Article  PubMed  PubMed Central  Google Scholar 

  35. Waibel M et al (2013) Combined targeting of JAK2 and Bcl-2/Bcl-xL to cure mutant JAK2-driven malignancies and overcome acquired resistance to JAK2 inhibitors. Cell Rep 5:1047–1059. https://doi.org/10.1016/j.celrep.2013.10.038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kontro M et al (2014) Novel activating STAT5B mutations as putative drivers of T-cell acute lymphoblastic leukemia. Leukemia 28:1738–1742. https://doi.org/10.1038/leu.2014.89

    Article  CAS  PubMed  Google Scholar 

  37. Janes MR et al (2010) Effective and selective targeting of leukemia cells using a TORC1/2 kinase inhibitor. Nat Med 16:205–213. https://doi.org/10.1038/nm.2091

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Fan QW et al (2006) A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma. Cancer Cell 9:341–349. https://doi.org/10.1016/j.ccr.2006.03.029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. O’Dwyer ME, Mauro MJ, Druker BJ (2002) Recent advancements in the treatment of chronic myelogenous leukemia. Annu Rev Med 53:369–381. https://doi.org/10.1146/annurev.med.53.082901.103853

    Article  PubMed  Google Scholar 

  40. Shah NP et al (2002) Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell 2:117–125

    Article  CAS  PubMed  Google Scholar 

  41. Shah NP, Sawyers CL (2003) Mechanisms of resistance to STI571 in Philadelphia chromosome-associated leukemias. Oncogene 22:7389–7395. https://doi.org/10.1038/sj.onc.1206942

    Article  CAS  PubMed  Google Scholar 

  42. Gorre ME et al (2001) Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293:876–880. https://doi.org/10.1126/science.1062538

    Article  CAS  PubMed  Google Scholar 

  43. Kantarjian H et al (2010) Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 362:2260–2270. https://doi.org/10.1056/NEJMoa1002315

    Article  CAS  PubMed  Google Scholar 

  44. Tran KA et al (2016) MEK inhibitors and their potential in the treatment of advanced melanoma: the advantages of combination therapy. Drug Des Devel Ther 10:43–52. https://doi.org/10.2147/DDDT.S93545

    Article  CAS  PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal

    João T. Barata & Mariana L. Oliveira

Authors
  1. João T. Barata
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  2. Mariana L. Oliveira
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Corresponding author

Correspondence to João T. Barata .

Editor information

Editors and Affiliations

  1. Champalimaud Centre for the Unknown, Champalimaud Foundation, Lisbon, Portugal

    Rita Fior

  2. Faculdade de Ciências da Universidade de Lisboa, Lisbon, Portugal

    Rita Zilhão

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Barata, J.T., Oliveira, M.L. (2019). Cell Signaling in Cancer. In: Fior, R., Zilhão, R. (eds) Molecular and Cell Biology of Cancer. Learning Materials in Biosciences. Springer, Cham. https://doi.org/10.1007/978-3-030-11812-9_3

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