Interrogating Resistance to Targeted Therapy Using Genetically Engineered Mouse Models of Cancer

Chapter
First Online:
Part of the Molecular and Translational Medicine book series (MOLEMED)

Abstract

With the advent of cancer genome sequencing and rationally designed targeted therapeutics, mouse models of human cancer might seem destined to become relics of a bygone era. Instead, the engineering of mouse genomes continues to evolve, yielding versatile and powerful research tools for modeling targeted therapy. Just as the first wave of cancer-prone transgenic mice helped unravel the genetic events driving tumor initiation and progression, a new wave of mouse models is helping unravel the molecular mechanisms whereby tumors respond to, and ultimately bypass, a blockade in oncogenic signaling. This chapter explores insights into drug resistance mechanisms gained using mouse models, as well as potential limitations associated with this approach.

Keywords

Targeted therapy Mouse Tumor escape Drug resistance Reversible 
This is a preview of subscription content, log in to check access.

References

  1. 1.
    Sawyers CL. Shifting paradigms: the seeds of oncogene addiction. Nat Med. 2009;15:1158–61.PubMedCrossRefGoogle Scholar
  2. 2.
    Chin L et al. Essential role for oncogenic Ras in tumour maintenance. Nature. 1999;400:468–72.PubMedCrossRefGoogle Scholar
  3. 3.
    Fisher GH et al. Induction and apoptotic regression of lung adenocarcinomas by regulation of a K-Ras transgene in the presence and absence of tumor suppressor genes. Genes Dev. 2001;15:3249–62.PubMedCrossRefGoogle Scholar
  4. 4.
    Pelengaris S, Littlewood T, Khan M, Elia G, Evan G. Reversible activation of c-Myc in skin: induction of a complex neoplastic phenotype by a single oncogenic lesion. Mol Cell. 1999;3:565–77.PubMedCrossRefGoogle Scholar
  5. 5.
    Weinstein IB. Cancer. Addiction to oncogenes – the Achilles heal of cancer. Science. 2002;297:63–4.PubMedCrossRefGoogle Scholar
  6. 6.
    Martins CP, Brown-Swigart L, Evan GI. Modeling the therapeutic efficacy of p53 restoration in tumors. Cell. 2006;127:1323–34.PubMedCrossRefGoogle Scholar
  7. 7.
    Ventura A et al. Restoration of p53 function leads to tumour regression in vivo. Nature. 2007;445:661–5.PubMedCrossRefGoogle Scholar
  8. 8.
    Xue W et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature. 2007;445:656–60.PubMedCrossRefGoogle Scholar
  9. 9.
    Kastan MB. Wild-type p53: tumors can’t stand it. Cell. 2007;128:837–40.PubMedCrossRefGoogle Scholar
  10. 10.
    Pelengaris S et al. Brief inactivation of c-Myc is not sufficient for sustained regression of c-Myc-induced tumours of pancreatic islets and skin epidermis. BMC Biol. 2004;2:26.PubMedCrossRefGoogle Scholar
  11. 11.
    Gunther EJ et al. Impact of p53 loss on reversal and recurrence of conditional Wnt-induced tumorigenesis. Genes Dev. 2003;17:488–501.PubMedCrossRefGoogle Scholar
  12. 12.
    Boxer RB, Jang JW, Sintasath L, Chodosh LA. Lack of sustained regression of c-MYC-induced mammary adenocarcinomas following brief or prolonged MYC inactivation. Cancer Cell. 2004;6:577–86.PubMedCrossRefGoogle Scholar
  13. 13.
    Moody SE et al. The transcriptional repressor Snail promotes mammary tumor recurrence. Cancer Cell. 2005;8:197–209.PubMedCrossRefGoogle Scholar
  14. 14.
    Chin L, DePinho RA. Flipping the oncogene switch: illumination of tumor maintenance and regression. Trends Genet. 2000;16:147–50.PubMedCrossRefGoogle Scholar
  15. 15.
    van Amerongen R, Berns A. Targeted anticancer therapies: mouse models help uncover the mechanisms of tumor escape. Cancer Cell. 2008;13:5–7.PubMedCrossRefGoogle Scholar
  16. 16.
    Vargo-Gogola T, Rosen JM. Modelling breast cancer: one size does not fit all. Nat Rev Cancer. 2007;7:659–72.PubMedCrossRefGoogle Scholar
  17. 17.
    Frese KK, Tuveson DA. Maximizing mouse cancer models. Nat Rev Cancer. 2007;7:645–58.PubMedCrossRefGoogle Scholar
  18. 18.
    Felsher DW. Cancer revoked: oncogenes as therapeutic targets. Nat Rev Cancer. 2003;3:375–80.PubMedCrossRefGoogle Scholar
  19. 19.
    Shachaf CM, Felsher DW. Rehabilitation of cancer through oncogene inactivation. Trends Mol Med. 2005;11:316–21.PubMedCrossRefGoogle Scholar
  20. 20.
    Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70.PubMedCrossRefGoogle Scholar
  21. 21.
    Pelengaris S, Khan M, Evan GI. Suppression of Myc-induced apoptosis in beta cells exposes multiple oncogenic properties of Myc and triggers carcinogenic progression. Cell. 2002;109:321–34.PubMedCrossRefGoogle Scholar
  22. 22.
    Evan GI, d’Adda di Fagagna F. Cellular senescence: hot or what? Curr Opin Genet Dev. 2009;19:25–31.PubMedCrossRefGoogle Scholar
  23. 23.
    Schmitt CA et al. A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy. Cell. 2002;109:335–46.PubMedCrossRefGoogle Scholar
  24. 24.
    Wu CH et al. Cellular senescence is an important mechanism of tumor regression upon c-Myc inactivation. Proc Natl Acad Sci USA. 2007;104:13028–33.PubMedCrossRefGoogle Scholar
  25. 25.
    Swartling FJ et al. Pleiotropic role for MYCN in medulloblastoma. Genes Dev. 2010;24:1059–72.PubMedCrossRefGoogle Scholar
  26. 26.
    van Riggelen J et al. The interaction between Myc and Miz1 is required to antagonize TGFbeta-dependent autocrine signaling during lymphoma formation and maintenance. Genes Dev. 2010;24:1281–94.PubMedCrossRefGoogle Scholar
  27. 27.
    Sarkisian CJ et al. Dose-dependent oncogene-induced senescence in vivo and its evasion during mammary tumorigenesis. Nat Cell Biol. 2007;9:493–505.PubMedCrossRefGoogle Scholar
  28. 28.
    Murphy DJ et al. Distinct thresholds govern Myc’s biological output in vivo. Cancer Cell. 2008;14:447–57.PubMedCrossRefGoogle Scholar
  29. 29.
    Jain M et al. Sustained loss of a neoplastic phenotype by brief inactivation of MYC. Science. 2002;297:102–4.PubMedCrossRefGoogle Scholar
  30. 30.
    Shachaf CM et al. MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer. Nature. 2004;431:1112–7.PubMedCrossRefGoogle Scholar
  31. 31.
    Michor F et al. Dynamics of chronic myeloid leukaemia. Nature. 2005;435:1267–70.PubMedCrossRefGoogle Scholar
  32. 32.
    Demicheli R, Biganzoli E, Boracchi P, Greco M, Retsky MW. Recurrence dynamics does not depend on the recurrence site. Breast Cancer Res. 2008;10:R83.PubMedCrossRefGoogle Scholar
  33. 33.
    Demicheli R. Tumour dormancy: findings and hypotheses from clinical research on breast cancer. Semin Cancer Biol. 2001;11:297–306.PubMedCrossRefGoogle Scholar
  34. 34.
    Uhr JW, Scheuermann RH, Street NE, Vitetta ES. Cancer dormancy: opportunities for new therapeutic approaches. Nat Med. 1997;3:505–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Aguirre-Ghiso JA. Models, mechanisms and clinical evidence for cancer dormancy. Nat Rev Cancer. 2007;7:834–46.PubMedCrossRefGoogle Scholar
  36. 36.
    Koebel CM et al. Adaptive immunity maintains occult cancer in an equilibrium state. Nature. 2007;450:903–7.PubMedCrossRefGoogle Scholar
  37. 37.
    Teng MW, Swann JB, Koebel CM, Schreiber RD, Smyth MJ. Immune-mediated dormancy: an equilibrium with cancer. J Leukoc Biol. 2008;84:988–93.PubMedCrossRefGoogle Scholar
  38. 38.
    Udagawa T, Fernandez A, Achilles EG, Folkman J, D’Amato RJ. Persistence of microscopic human cancers in mice: alterations in the angiogenic balance accompanies loss of tumor dormancy. FASEB J. 2002;16:1361–70.PubMedCrossRefGoogle Scholar
  39. 39.
    Watnick RS, Cheng YN, Rangarajan A, Ince TA, Weinberg RA. Ras modulates Myc activity to repress thrombospondin-1 expression and increase tumor angiogenesis. Cancer Cell. 2003;3:219–31.PubMedCrossRefGoogle Scholar
  40. 40.
    Coller HA, Sang L, Roberts JM. A new description of cellular quiescence. PLoS Biol. 2006;4:e83.PubMedCrossRefGoogle Scholar
  41. 41.
    Harmes DC, DiRenzo J. Cellular quiescence in mammary stem cells and breast tumor stem cells: got testable hypotheses? J Mammary Gland Biol Neoplasia. 2009;14:19–27.PubMedCrossRefGoogle Scholar
  42. 42.
    Gestl SA, Leonard TL, Biddle JL, Debies MT, Gunther EJ. Dormant Wnt-initiated mammary cancer can participate in reconstituting functional mammary glands. Mol Cell Biol. 2007;27:195–207.PubMedCrossRefGoogle Scholar
  43. 43.
    Jechlinger M, Podsypanina K, Varmus H. Regulation of transgenes in three-dimensional ­cultures of primary mouse mammary cells demonstrates oncogene dependence and identifies cells that survive deinduction. Genes Dev. 2009;23:1677–88.PubMedCrossRefGoogle Scholar
  44. 44.
    Kaelin Jr WG. Gleevec: prototype or outlier? Sci STKE. 2004;2004:12.CrossRefGoogle Scholar
  45. 45.
    Stratton MR, Campbell PJ, Futreal PA. The cancer genome. Nature. 2009;458:719–24.PubMedCrossRefGoogle Scholar
  46. 46.
    Gorre ME et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science. 2001;293:876–80.PubMedCrossRefGoogle Scholar
  47. 47.
    Shah NP et al. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science. 2004;305:399–401.PubMedCrossRefGoogle Scholar
  48. 48.
    Lynch TJ et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350:2129–39.PubMedCrossRefGoogle Scholar
  49. 49.
    Paez JG et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304:1497–500.PubMedCrossRefGoogle Scholar
  50. 50.
    Pao W et al. EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci USA. 2004;101:13306–11.PubMedCrossRefGoogle Scholar
  51. 51.
    Kobayashi S et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med. 2005;352:786–92.PubMedCrossRefGoogle Scholar
  52. 52.
    Pao W et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2005;2:e73.PubMedCrossRefGoogle Scholar
  53. 53.
    Ji H et al. The impact of human EGFR kinase domain mutations on lung tumorigenesis and in vivo sensitivity to EGFR-targeted therapies. Cancer Cell. 2006;9:485–95.PubMedCrossRefGoogle Scholar
  54. 54.
    Politi K et al. Lung adenocarcinomas induced in mice by mutant EGF receptors found in human lung cancers respond to a tyrosine kinase inhibitor or to down-regulation of the ­receptors. Genes Dev. 2006;20:1496–510.PubMedCrossRefGoogle Scholar
  55. 55.
    Regales L et al. Development of new mouse lung tumor models expressing EGFR T790M mutants associated with clinical resistance to kinase inhibitors. PLoS One. 2007;2:e810.PubMedCrossRefGoogle Scholar
  56. 56.
    Li D et al. Bronchial and peripheral murine lung carcinomas induced by T790M-L858R mutant EGFR respond to HKI-272 and rapamycin combination therapy. Cancer Cell. 2007;12:81–93.PubMedCrossRefGoogle Scholar
  57. 57.
    Sawai A et al. Inhibition of Hsp90 down-regulates mutant epidermal growth factor receptor (EGFR) expression and sensitizes EGFR mutant tumors to paclitaxel. Cancer Res. 2008;68:589–96.PubMedCrossRefGoogle Scholar
  58. 58.
    Regales L et al. Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer. J Clin Invest. 2009;119:3000–10.PubMedGoogle Scholar
  59. 59.
    Politi K, Fan PD, Shen R, Zakowski M, Varmus H. Erlotinib resistance in mouse models of epidermal growth factor receptor-induced lung adenocarcinoma. Dis Model Mech. 2010;3:111–9.PubMedCrossRefGoogle Scholar
  60. 60.
    Engelman JA et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science. 2007;316:1039–43.PubMedCrossRefGoogle Scholar
  61. 61.
    Bean J et al. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci USA. 2007;104:20932–7.PubMedCrossRefGoogle Scholar
  62. 62.
    Sharma SV, Settleman J. Oncogene addiction: setting the stage for molecularly targeted ­cancer therapy. Genes Dev. 2007;21:3214–31.PubMedCrossRefGoogle Scholar
  63. 63.
    Debies MT et al. Tumor escape in a Wnt1-dependent mouse breast cancer model is enabled by p19Arf/p53 pathway lesions but not p16 Ink4a loss. J Clin Invest. 2008;118:51–63.PubMedCrossRefGoogle Scholar
  64. 64.
    Podsypanina K, Politi K, Beverly LJ, Varmus HE. Oncogene cooperation in tumor maintenance and tumor recurrence in mouse mammary tumors induced by Myc and mutant Kras. Proc Natl Acad Sci USA. 2008;105:5242–7.PubMedCrossRefGoogle Scholar
  65. 65.
    Giuriato S et al. Sustained regression of tumors upon MYC inactivation requires p53 or thrombospondin-1 to reverse the angiogenic switch. Proc Natl Acad Sci USA. 2006;103:16266–71.PubMedCrossRefGoogle Scholar
  66. 66.
    Mani SA et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133:704–15.PubMedCrossRefGoogle Scholar
  67. 67.
    Creighton CJ et al. Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proc Natl Acad Sci USA. 2009;106:13820–5.PubMedCrossRefGoogle Scholar
  68. 68.
    Williams RT, Roussel MF, Sherr CJ. Arf gene loss enhances oncogenicity and limits imatinib response in mouse models of Bcr-Abl-induced acute lymphoblastic leukemia. Proc Natl Acad Sci USA. 2006;103:6688–93.PubMedCrossRefGoogle Scholar
  69. 69.
    Williams RT, den Besten W, Sherr CJ. Cytokine-dependent imatinib resistance in mouse BCR-ABL+, Arf-null lymphoblastic leukemia. Genes Dev. 2007;21:2283–7.PubMedCrossRefGoogle Scholar
  70. 70.
    Dorshkind K, Witte ON. Linking the hematopoietic microenvironment to imatinib-resistant Ph+ B-ALL. Genes Dev. 2007;21:2249–52.PubMedCrossRefGoogle Scholar
  71. 71.
    Sharma SV et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell. 2010;141:69–80.PubMedCrossRefGoogle Scholar
  72. 72.
    Krizhanovsky V, Lowe SW. Stem cells: the promises and perils of p53. Nature. 2009;460:1085–6.PubMedCrossRefGoogle Scholar
  73. 73.
    Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer. 2009;9:265–73.PubMedCrossRefGoogle Scholar
  74. 74.
    Pao W, Klimstra DS, Fisher GH, Varmus HE. Use of avian retroviral vectors to introduce transcriptional regulators into mammalian cells for analyses of tumor maintenance. Proc Natl Acad Sci USA. 2003;100:8764–9.PubMedCrossRefGoogle Scholar
  75. 75.
    Miething C et al. Retroviral insertional mutagenesis identifies RUNX genes involved in chronic myeloid leukemia disease persistence under imatinib treatment. Proc Natl Acad Sci USA. 2007;104:4594–9.PubMedCrossRefGoogle Scholar
  76. 76.
    Lauchle JO et al. Response and resistance to MEK inhibition in leukaemias initiated by hyperactive Ras. Nature. 2009;461:411–4.PubMedCrossRefGoogle Scholar
  77. 77.
    Largaespada DA. Transposon-mediated mutagenesis of somatic cells in the mouse for cancer gene identification. Methods. 2009;49:282–6.PubMedCrossRefGoogle Scholar
  78. 78.
    Sotillo R, Schvartzman JM, Socci ND, Benezra R. Mad2-induced chromosome instability leads to lung tumour relapse after oncogene withdrawal. Nature. 2010;464:436–40.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of MedicinePennsylvania State College of MedicineHersheyUSA
  2. 2.Jake Gittlen Cancer Research FoundationPennsylvania State College of MedicineHersheyUSA

Personalised recommendations