SpringerLink
Log in

Targeting ALK: a promising strategy for the treatment of non-small cell lung cancer, non-Hodgkin’s lymphoma, and neuroblastoma

  • Review
  • Published:
Targeted Oncology Aims and scope Submit manuscript

An Erratum to this article was published on 08 September 2013

Abstract

Anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor that affects a number of biological and biochemical functions through normal ligand-dependent signaling. It has oncogenic functions in a number of tumors including non-small cell lung cancer (NSCLC), anaplastic large cell lymphoma, and neuroblastoma when altered by translocation or amplification or mutation. On August 2011, a small molecule inhibitor against ALK, crizotinib, was approved for therapy against NSCLC with ALK translocations. As we determine the molecular heterogeneity of tumors, the potential of ALK as a relevant therapeutic target in a number of malignancies has become apparent. This review will discuss some of the tumor types with oncogenic ALK alterations. The activity and unique toxicities of crizotinib are described, along with potential mechanisms of resistance and new therapies beyond crizotinib.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Morris SW, Kirstein MN, Valentine MB, Dittmer KG, Shapiro DN, Saltman DL et al (1994) Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. Science 263(5151):1281–1284

    Article  PubMed  CAS  Google Scholar 

  2. Azarova AM, Gautam G, George RE (2011) Emerging importance of ALK in neuroblastoma. Semin Cancer Biol 21(4):267–275

    Article  PubMed  CAS  Google Scholar 

  3. Webb TR, Slavish J, George RE, Look AT, Xue L, Jiang Q et al (2009) Anaplastic lymphoma kinase: role in cancer pathogenesis and small-molecule inhibitor development for therapy. Expert Rev Anticancer Ther 9(3):331–356

    Article  PubMed  CAS  Google Scholar 

  4. Lee CC, Jia Y, Li N, Sun X, Ng K, Ambing E et al (2010) Crystal structure of the ALK (anaplastic lymphoma kinase) catalytic domain. Biochem J 430(3):425–437

    Article  PubMed  CAS  Google Scholar 

  5. Tartari CJ, Gunby RH, Coluccia AM, Sottocornola R, Cimbro B, Scapozza L et al (2008) Characterization of some molecular mechanisms governing autoactivation of the catalytic domain of the anaplastic lymphoma kinase. J Biol Chem 283(7):3743–3750

    Article  PubMed  CAS  Google Scholar 

  6. Iwahara T, Fujimoto J, Wen D, Cupples R, Bucay N, Arakawa T et al (1997) Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system. Oncogene 14(4):439–449

    Article  PubMed  CAS  Google Scholar 

  7. The human protein atlas. Electronic citation 2012 Available from: www.proteinatlas.org

  8. Stoica GE, Kuo A, Aigner A, Sunitha I, Souttou B, Malerczyk C et al (2001) Identification of anaplastic lymphoma kinase as a receptor for the growth factor pleiotrophin. J Biol Chem 276(20):16772–16779

    Article  PubMed  CAS  Google Scholar 

  9. Powers C, Aigner A, Stoica GE, McDonnell K, Wellstein A (2002) Pleiotrophin signaling through anaplastic lymphoma kinase is rate-limiting for glioblastoma growth. J Biol Chem 277(16):14153–14158

    Article  PubMed  CAS  Google Scholar 

  10. Miyake I, Hakomori Y, Shinohara A, Gamou T, Saito M, Iwamatsu A et al (2002) Activation of anaplastic lymphoma kinase is responsible for hyperphosphorylation of ShcC in neuroblastoma cell lines. Oncogene 21(38):5823–5834

    Article  PubMed  CAS  Google Scholar 

  11. Mourali J, Benard A, Lourenco FC, Monnet C, Greenland C, Moog-Lutz C et al (2006) Anaplastic lymphoma kinase is a dependence receptor whose proapoptotic functions are activated by caspase cleavage. Mol Cell Biol 26(16):6209–6222

    Article  PubMed  CAS  Google Scholar 

  12. Catalog of somatic mutations in cancer. Electronic citation 2012 Available from: http://www.sanger.ac.uk/perl/genetics/CGP/cosmic?action=gene&ln=ALK

  13. Catlog of somatic mutations in cancer. Electronic citation 2012 Available from: http://www.sanger.ac.uk/perl/genetics/CGP/cosmic?action=bygene&ln=ALK&start=1&end=1621&coords=AA:AA

  14. Siegel R, Ward E, Brawley O, Jemal A (2011) Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 61(4):212–236

    Article  PubMed  Google Scholar 

  15. Lung cancer—National Cancer Institute. Electronic citation 2012 Available from: http://www.cancer.gov/cancertopics/types/lung

  16. Cancer of the lungs and bronchus—SEER Stat Fact Sheets. Electronic citation 2012 Available from: http://seer.cancer.gov/statfacts/html/lungb.html

  17. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A et al (2006) Paclitaxel–carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355(24):2542–2550

    Article  PubMed  CAS  Google Scholar 

  18. Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C et al. (2008) Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 26(21):3543–3551

    Google Scholar 

  19. Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S et al (2007) Identification of the transforming EML4–ALK fusion gene in non-small-cell lung cancer. Nature 448(7153):561–566

    Article  PubMed  CAS  Google Scholar 

  20. Horn L, Pao W (2009) EML4–ALK: honing in on a new target in non-small-cell lung cancer. J Clin Oncol 27(26):4232–4235

    Article  PubMed  CAS  Google Scholar 

  21. Sasaki T, Rodig SJ, Chirieac LR, Janne PA (2010) The biology and treatment of EML4-ALK non-small cell lung cancer. Eur J Cancer 46(10):1773–1780

    Article  PubMed  CAS  Google Scholar 

  22. Soda M, Takada S, Takeuchi K, Choi YL, Enomoto M, Ueno T et al (2008) A mouse model for EML4–ALK-positive lung cancer. Proc Natl Acad Sci U S A 105(50):19893–19897

    Article  PubMed  CAS  Google Scholar 

  23. Shaw AT, Yeap BY, Mino-Kenudson M, Digumarthy SR, Costa DB, Heist RS et al (2009) Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4–ALK. J Clin Oncol 27(26):4247–4253

    Article  PubMed  CAS  Google Scholar 

  24. Shaw AT et al. Prognostic versus predictive value of EML4–ALK translocation in metastatic non-small cell lung cancer. J Clin Oncol 28. 4-3-2010. Ref Type: Abstract

  25. Martinez P et al. ALK rearrangement in a selected population of advanced non-small cell lung cancer patients: FISH and inmunohistochemistry diagnostic methods, prevalence, and clinical outcomes. J Clin Oncol 29. 6-1-2011. Ref Type: Abstract

  26. Rosell R, Moran T, Queralt C, Porta R, Cardenal F, Camps C et al (2009) Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 361(10):958–967

    Article  PubMed  CAS  Google Scholar 

  27. Kim ES, Salgia R (2009) MET pathway as a therapeutic target. J Thorac Oncol 4(4):444–447

    Article  PubMed  Google Scholar 

  28. Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B, Maki RG et al (2010) Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 363(18):1693–1703

    Article  PubMed  CAS  Google Scholar 

  29. Shaw AT, Yeap BY, Solomon BJ, Riely GJ, Gainor J, Engelman JA et al (2011) Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis. Lancet Oncol 12(11):1004–1012

    Article  PubMed  CAS  Google Scholar 

  30. Shaw AT et al. Impact of crizotinib on survival in patients with advanced, ALK-positive NSCLC compared with historical controls. J Clin Oncol 29. 3-12-2011. Ref Type: Abstract

  31. Weickhardt AJ, Rothman MS, Salian-Mehta S, Kiseljak-Vassiliades K, Oton AB, Doebele RC et al. (2012) Rapid-onset hypogonadism secondary to crizotinib use in men with metastatic non-small cell lung cancer. Cancer. doi:10.1002/cncr.27450

  32. Heuckmann JM, Holzel M, Sos ML, Heynck S, Balke-Want H, Koker M et al (2011) ALK mutations conferring differential resistance to structurally diverse ALK inhibitors. Clin Cancer Res 17(23):7394–7401

    Article  PubMed  CAS  Google Scholar 

  33. A clinical trial testing the efficacy of crizotinib versus standard chemotherapy pemetrexed plus cisplatin or carboplatin in patients with ALK positive non-squamous cancer of the lung. Electronic citation 2012 Available from: http://clinicaltrials.gov/ct2/show/NCT01154140?term=alk+pemetrexed&rank=2

  34. Swerdlow S, Campo E, Harris NL et al. (2008) WHO classification of tumours of haematopoietic and lymphoid tissues, 4th edn. World Health Organization, Lyon

  35. Vose J, Armitage J, Weisenburger D (2008) International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol 26(25):4124–4130

    Article  PubMed  Google Scholar 

  36. Savage KJ, Harris NL, Vose JM, Ullrich F, Jaffe ES, Connors JM et al (2008) ALK− anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project. Blood 111(12):5496–5504

    Article  PubMed  CAS  Google Scholar 

  37. Lamant L, de Reynies A, Duplantier MM, Rickman DS, Sabourdy F, Giuriato S et al (2007) Gene-expression profiling of systemic anaplastic large-cell lymphoma reveals differences based on ALK status and two distinct morphologic ALK+ subtypes. Blood 109(5):2156–2164

    Article  PubMed  CAS  Google Scholar 

  38. Salaverria I, Bea S, Lopez-Guillermo A, Lespinet V, Pinyol M, Burkhardt B et al (2008) Genomic profiling reveals different genetic aberrations in systemic ALK-positive and ALK-negative anaplastic large cell lymphomas. Br J Haematol 140(5):516–526

    Article  PubMed  Google Scholar 

  39. Thompson MA, Stumph J, Henrickson SE, Rosenwald A, Wang Q, Olson S et al (2005) Differential gene expression in anaplastic lymphoma kinase-positive and anaplastic lymphoma kinase-negative anaplastic large cell lymphomas. Hum Pathol 36(5):494–504

    Article  PubMed  CAS  Google Scholar 

  40. Shiota M, Nakamura S, Ichinohasama R, Abe M, Akagi T, Takeshita M et al (1995) Anaplastic large cell lymphomas expressing the novel chimeric protein p80NPM/ALK: a distinct clinicopathologic entity. Blood 86(5):1954–1960

    PubMed  CAS  Google Scholar 

  41. Shiota M, Fujimoto J, Semba T, Satoh H, Yamamoto T, Mori S (1994) Hyperphosphorylation of a novel 80 kDa protein-tyrosine kinase similar to Ltk in a human Ki-1 lymphoma cell line, AMS3. Oncogene 9(6):1567–1574

    PubMed  CAS  Google Scholar 

  42. Amin HM, Lai R (2007) Pathobiology of ALK+ anaplastic large-cell lymphoma. Blood 110(7):2259–2267

    Article  PubMed  CAS  Google Scholar 

  43. Chiarle R, Voena C, Ambrogio C, Piva R, Inghirami G (2008) The anaplastic lymphoma kinase in the pathogenesis of cancer. Nat Rev Cancer 8(1):11–23

    Article  PubMed  CAS  Google Scholar 

  44. Kuefer MU, Look AT, Pulford K, Behm FG, Pattengale PK, Mason DY et al (1997) Retrovirus-mediated gene transfer of NPM–ALK causes lymphoid malignancy in mice. Blood 90(8):2901–2910

    PubMed  CAS  Google Scholar 

  45. Wasik MA, Zhang Q, Marzec M, Kasprzycka M, Wang HY, Liu X (2009) Anaplastic lymphoma kinase (ALK)-induced malignancies: novel mechanisms of cell transformation and potential therapeutic approaches. Semin Oncol 36(2 Suppl 1):S27–S35

    Article  PubMed  CAS  Google Scholar 

  46. Chiarle R, Simmons WJ, Cai H, Dhall G, Zamo A, Raz R et al (2005) Stat3 is required for ALK-mediated lymphomagenesis and provides a possible therapeutic target. Nat Med 11(6):623–629

    Article  PubMed  CAS  Google Scholar 

  47. Zamo A, Chiarle R, Piva R, Howes J, Fan Y, Chilosi M et al (2002) Anaplastic lymphoma kinase (ALK) activates Stat3 and protects hematopoietic cells from cell death. Oncogene 21(7):1038–1047

    Article  PubMed  CAS  Google Scholar 

  48. Marzec M, Kasprzycka M, Ptasznik A, Wlodarski P, Zhang Q, Odum N et al (2005) Inhibition of ALK enzymatic activity in T-cell lymphoma cells induces apoptosis and suppresses proliferation and STAT3 phosphorylation independently of Jak3. Lab Invest 85(12):1544–1554

    PubMed  CAS  Google Scholar 

  49. Zhang Q, Wang HY, Marzec M, Raghunath PN, Nagasawa T, Wasik MA (2005) STAT3- and DNA methyltransferase 1-mediated epigenetic silencing of SHP-1 tyrosine phosphatase tumor suppressor gene in malignant T lymphocytes. Proc Natl Acad Sci U S A 102(19):6948–6953

    Article  PubMed  CAS  Google Scholar 

  50. Zhang Q, Wang HY, Woetmann A, Raghunath PN, Odum N, Wasik MA (2006) STAT3 induces transcription of the DNA methyltransferase 1 gene (DNMT1) in malignant T lymphocytes. Blood 108(3):1058–1064

    Article  PubMed  CAS  Google Scholar 

  51. Slupianek A, Nieborowska-Skorska M, Hoser G, Morrione A, Majewski M, Xue L et al (2001) Role of phosphatidylinositol 3-kinase-Akt pathway in nucleophosmin/anaplastic lymphoma kinase-mediated lymphomagenesis. Cancer Res 61(5):2194–2199

    PubMed  CAS  Google Scholar 

  52. Vega F, Medeiros LJ, Leventaki V, Atwell C, Cho-Vega JH, Tian L et al (2006) Activation of mammalian target of rapamycin signaling pathway contributes to tumor cell survival in anaplastic lymphoma kinase-positive anaplastic large cell lymphoma. Cancer Res 66(13):6589–6597

    Article  PubMed  CAS  Google Scholar 

  53. Marzec M, Kasprzycka M, Liu X, El-Salem M, Halasa K, Raghunath PN et al (2007) Oncogenic tyrosine kinase NPM/ALK induces activation of the rapamycin-sensitive mTOR signaling pathway. Oncogene 26(38):5606–5614

    Article  PubMed  CAS  Google Scholar 

  54. McDonnell SR, Hwang SR, Basrur V, Conlon KP, Fermin D, Wey E et al. (2011) NPM–ALK signals through glycogen synthase kinase 3beta to promote oncogenesis. Oncogene. doi:10.1038/onc.2011.542

  55. Schmitz N, Trumper L, Ziepert M, Nickelsen M, Ho AD, Metzner B et al (2010) Treatment and prognosis of mature T-cell and NK-cell lymphoma: an analysis of patients with T-cell lymphoma treated in studies of the German High-Grade Non-Hodgkin Lymphoma Study Group. Blood 116(18):3418–3425

    Article  PubMed  CAS  Google Scholar 

  56. Skarbnik AP, Smith MR (2012) Brentuximab vedotin in anaplastic large cell lymphoma. Expert Opin Biol Ther 12(5):633–639

    Article  PubMed  CAS  Google Scholar 

  57. Younes A, Bartlett NL, Leonard JP, Kennedy DA, Lynch CM, Sievers EL et al (2010) Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med 363(19):1812–1821

    Article  PubMed  CAS  Google Scholar 

  58. Lowe EJ, Sposto R, Perkins SL, Gross TG, Finlay J, Zwick D et al (2009) Intensive chemotherapy for systemic anaplastic large cell lymphoma in children and adolescents: final results of Children's Cancer Group Study 5941. Pediatr Blood Cancer 52(3):335–339

    Article  PubMed  Google Scholar 

  59. Gambacorti-Passerini C, Messa C, Pogliani EM (2011) Crizotinib in anaplastic large-cell lymphoma. N Engl J Med 364(8):775–776

    Article  PubMed  Google Scholar 

  60. Delsol G, Lamant L, Mariame B, Pulford K, Dastugue N, Brousset P et al (1997) A new subtype of large B-cell lymphoma expressing the ALK kinase and lacking the 2; 5 translocation. Blood 89(5):1483–1490

    PubMed  CAS  Google Scholar 

  61. Laurent C, Do C, Gascoyne RD, Lamant L, Ysebaert L, Laurent G et al (2009) Anaplastic lymphoma kinase-positive diffuse large B-cell lymphoma: a rare clinicopathologic entity with poor prognosis. J Clin Oncol 27(25):4211–4216

    Article  PubMed  Google Scholar 

  62. Gascoyne RD, Lamant L, Martin-Subero JI, Lestou VS, Harris NL, Muller-Hermelink HK et al (2003) ALK-positive diffuse large B-cell lymphoma is associated with Clathrin-ALK rearrangements: report of 6 cases. Blood 102(7):2568–2573

    Article  PubMed  CAS  Google Scholar 

  63. De Paepe P, Baens M, van Krieken H, Verhasselt B, Stul M, Simons A et al. (2003) ALK activation by the CLTC–ALK fusion is a recurrent event in large B-cell lymphoma. Blood 102(7):2638–2641

    Google Scholar 

  64. Cerchietti L, Damm-Welk C, Vater I, Klapper W, Harder L, Pott C et al. (2011) Inhibition of anaplastic lymphoma kinase (ALK) activity provides a therapeutic approach for CLTC–ALK-positive human diffuse large B cell lymphomas. PLoS One 6(4):e18436

    Google Scholar 

  65. Beltran B, Castillo J, Salas R, Quinones P, Morales D, Hurtado F et al (2009) ALK-positive diffuse large B-cell lymphoma: report of four cases and review of the literature. J Hematol Oncol 2:11

    Article  PubMed  Google Scholar 

  66. Maris JM, Hogarty MD, Bagatell R, Cohn SL (2007) Neuroblastoma. Lancet 369(9579):2106–2120

    Article  PubMed  CAS  Google Scholar 

  67. Brodeur GM, Seeger RC, Schwab M, Varmus HE, Bishop JM (1984) Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage. Science 224(4653):1121–1124

    Article  PubMed  CAS  Google Scholar 

  68. Seeger RC, Brodeur GM, Sather H, Dalton A, Siegel SE, Wong KY et al (1985) Association of multiple copies of the N-myc oncogene with rapid progression of neuroblastomas. N Engl J Med 313(18):1111–1116

    Article  PubMed  CAS  Google Scholar 

  69. Brodeur GM, Green AA, Hayes FA, Williams KJ, Williams DL, Tsiatis AA (1981) Cytogenetic features of human neuroblastomas and cell lines. Cancer Res 41(11 Pt 1):4678–4686

    PubMed  CAS  Google Scholar 

  70. George RE, Attiyeh EF, Li S, Moreau LA, Neuberg D, Li C et al (2007) Genome-wide analysis of neuroblastomas using high-density single nucleotide polymorphism arrays. PLoS One 2(2):e255

    Article  PubMed  Google Scholar 

  71. Mosse YP, Laudenslager M, Longo L, Cole KA, Wood A, Attiyeh EF et al (2008) Identification of ALK as a major familial neuroblastoma predisposition gene. Nature 455(7215):930–935

    Article  PubMed  CAS  Google Scholar 

  72. Ogawa S, Takita J, Sanada M, Hayashi Y (2011) Oncogenic mutations of ALK in neuroblastoma. Cancer Sci 102(2):302–308

    Article  PubMed  CAS  Google Scholar 

  73. Janoueix-Lerosey I, Lequin D, Brugieres L, Ribeiro A, de Pontual L, Combaret V et al. (2008) Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma. Nature 455(7215):967–970

    Google Scholar 

  74. Chen Y, Takita J, Choi YL, Kato M, Ohira M, Sanada M et al (2008) Oncogenic mutations of ALK kinase in neuroblastoma. Nature 455(7215):971–974

    Article  PubMed  CAS  Google Scholar 

  75. George RE, Sanda T, Hanna M, Frohling S, Luther W, Zhang J et al (2008) Activating mutations in ALK provide a therapeutic target in neuroblastoma. Nature 455(7215):975–978

    Article  PubMed  CAS  Google Scholar 

  76. Bresler SC, Wood AC, Haglund EA, Courtright J, Belcastro LT, Plegaria JS et al. (2011) Differential inhibitor sensitivity of anaplastic lymphoma kinase variants found in neuroblastoma. Sci Transl Med 3(108):108ra114

    Google Scholar 

  77. De BS, De PK, Kumps C, Zabrocki P, Porcu M, Westerhout EM et al (2010) Meta-analysis of neuroblastomas reveals a skewed ALK mutation spectrum in tumors with MYCN amplification. Clin Cancer Res 16(17):4353–4362

    Article  Google Scholar 

  78. Schulte JH, Bachmann HS, Brockmeyer B, Depreter K, Oberthur A, Ackermann S et al (2011) High ALK receptor tyrosine kinase expression supersedes ALK mutation as a determining factor of an unfavorable phenotype in primary neuroblastoma. Clin Cancer Res 17(15):5082–5092

    Article  PubMed  CAS  Google Scholar 

  79. Passoni L, Longo L, Collini P, Coluccia AM, Bozzi F, Podda M et al (2009) Mutation-independent anaplastic lymphoma kinase overexpression in poor prognosis neuroblastoma patients. Cancer Res 69(18):7338–7346

    Article  PubMed  CAS  Google Scholar 

  80. Weiser D, Laudenslager M, Rappaport E, Carpenter E, Attiyeh EF, Diskin S et al. Stratification of patients with neuroblastoma for targeted ALK inhibitor therapy. J Clin Oncol 29. 6-6-2011. Ref Type: Abstract

  81. Crizotinib in treating young patients with relapsed or refractory solid tumors or anaplastic large cell lymphoma. Electronic citation 2012 Available from: http://clinicaltrials.gov/ct2/show/NCT00939770?term=NCT00939770&rank=1

  82. Doebele RC, Pilling AB, Aisner DL, Kutateladze TG, Le AT, Weickhardt AJ et al (2012) Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res 18(5):1472–1482

    Article  PubMed  CAS  Google Scholar 

  83. Camidge DR, Doebele RC (2012) Treating ALK-positive lung cancer—early successes and future challenges. Nat Rev Clin Oncol 9:268–277

    Google Scholar 

  84. Lovly CM, Pao W (2012) Esca** ALK inhibition: mechanisms of and strategies to overcome resistance. Sci Transl Med 4(120):120ps2

    Google Scholar 

  85. Katayama R, Shaw AT, Khan TM, Mino-Kenudson M, Solomon BJ, Halmos B et al. (2012) Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers. Sci Transl Med 4(120):120ra17

    Google Scholar 

  86. Deng X, Wang J, Zhang J, Sim T, Kim ND, Sasaki T et al (2011) Discovery of 3,5-diamino-1,2,4-triazole ureas as potent anaplastic lymphoma kinase inhibitors. ACS Med Chem Lett 2(5):379–384

    Article  PubMed  CAS  Google Scholar 

  87. A first in patient, study of investigational drug PF-03446962 in patients with advanced solid tumors. Electronic citation 2012 Available from: http://clinicaltrials.gov/ct2/show/NCT00557856?term=PF-03446962&rank=2

  88. A dose finding study with oral LDK378 in patients with tumors characterized by genetic abnormalities in anaplastic lymphoma kinase (ALK). Electronic citation 2012 Available from: http://clinicaltrials.gov/ct2/show/NCT01283516?term=ldk+378&rank=1

  89. Study of an investigational drug, ASP3026, in patients with solid tumors. Electronic citation 2012 Available from: http://clinicaltrials.gov/ct2/show/NCT01401504?term=asp3026&rank=1

  90. EML4–ALK mutation: consider Xalkori. Electronic citation 2012 Available from: http://www.collabrx.com/lung/lookup?subtype_3.1*no_others_3.1

  91. West L, Vidwans SJ, Campbell NP, Shrager J, Simon GR, Bueno R et al (2012) A novel classification of lung cancer into molecular subtypes. PLoS One 7(2):e31906

    Article  PubMed  CAS  Google Scholar 

  92. A phase 1/2 study of the oral ALK/EGFR inhibitor AP26113. Electronic citation 2012 Available from: http://clinicaltrials.gov/ct2/show/NCT01449461?term=ap26113&rank=1

  93. Carpenter EHE, Chow A, Christensen J, Maris J, Mosse Y. Mechanisms of resistance to small molecule inhibition of anaplastic lymphoma kinase in human neuroblastoma. Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research Abstract 742. 4-1-2011. Ref Type: Abstract

  94. Paolo D, Brignole C, Pastorino F, Carosio R, Zorzoli A, Rossi M et al (2011) Neuroblastoma-targeted nanoparticles entrap** siRNA specifically knockdown ALK. Mol Ther 19(6):1131–1140

    Article  PubMed  Google Scholar 

  95. Bonvini P, Gastaldi T, Falini B, Rosolen A (2002) Nucleophosmin–anaplastic lymphoma kinase (NPM–ALK), a novel Hsp90-client tyrosine kinase: down-regulation of NPM–ALK expression and tyrosine phosphorylation in ALK(+) CD30(+) lymphoma cells by the Hsp90 antagonist 17-allylamino,17-demethoxygeldanamycin. Cancer Res 62(5):1559–1566

    PubMed  CAS  Google Scholar 

  96. Crizotinib and STA-9090 in ALK positive lung cancers. Electronic citation 2012 Available from: http://clinicaltrials.gov/ct2/show/NCT01579994?term=STA9090&rank=9

  97. Sequist LV, Gettinger S, Senzer NN, Martins RG, Janne PA, Lilenbaum R et al (2010) Activity of IPI-504, a novel heat-shock protein 90 inhibitor, in patients with molecularly defined non-small-cell lung cancer. J Clin Oncol 28(33):4953–4960

    Article  PubMed  CAS  Google Scholar 

  98. Chen Z, Sasaki T, Tan X, Carretero J, Shimamura T, Li D et al (2010) Inhibition of ALK, PI3K/MEK, and HSP90 in murine lung adenocarcinoma induced by EML4–ALK fusion oncogene. Cancer Res 70(23):9827–9836

    Article  PubMed  CAS  Google Scholar 

  99. Inamura K, Takeuchi K, Togashi Y, Nomura K, Ninomiya H, Okui M et al (2008) EML4–ALK fusion is linked to histological characteristics in a subset of lung cancers. J Thorac Oncol 3(1):13–17

    Article  PubMed  Google Scholar 

  100. Inamura K, Takeuchi K, Togashi Y, Hatano S, Ninomiya H, Motoi N et al (2009) EML4–ALK lung cancers are characterized by rare other mutations, a TTF-1 cell lineage, an acinar histology, and young onset. Mod Pathol 22(4):508–515

    Article  PubMed  CAS  Google Scholar 

  101. Koivunen JP, Mermel C, Zejnullahu K, Murphy C, Lifshits E, Holmes AJ et al (2008) EML4–ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin Cancer Res 14(13):4275–4283

    Article  PubMed  CAS  Google Scholar 

  102. Shinmura K, Kageyama S, Tao H, Bunai T, Suzuki M, Kamo T et al (2008) EML4–ALK fusion transcripts, but no NPM–, TPM3–, CLTC–, ATIC–, or TFG–ALK fusion transcripts, in non-small cell lung carcinomas. Lung Cancer 61(2):163–169

    Article  PubMed  Google Scholar 

  103. Martelli MP, Sozzi G, Hernandez L, Pettirossi V, Navarro A, Conte D et al (2009) EML4–ALK rearrangement in non-small cell lung cancer and non-tumor lung tissues. Am J Pathol 174(2):661–670

    Article  PubMed  CAS  Google Scholar 

  104. Wong DW, Leung EL, So KK, Tam IY, Sihoe AD, Cheng LC et al (2009) The EML4–ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS. Cancer 115(8):1723–1733

    Article  PubMed  CAS  Google Scholar 

  105. Takeuchi K, Choi YL, Togashi Y, Soda M, Hatano S, Inamura K et al (2009) KIF5B–ALK, a novel fusion oncokinase identified by an immunohistochemistry-based diagnostic system for ALK-positive lung cancer. Clin Cancer Res 15(9):3143–3149

    Article  PubMed  CAS  Google Scholar 

  106. Choi YL, Takeuchi K, Soda M, Inamura K, Togashi Y, Hatano S et al (2008) Identification of novel isoforms of the EML4–ALK transforming gene in non-small cell lung cancer. Cancer Res 68(13):4971–4976

    Article  PubMed  CAS  Google Scholar 

  107. Takeuchi K, Choi YL, Soda M, Inamura K, Togashi Y, Hatano S et al (2008) Multiplex reverse transcription–PCR screening for EML4–ALK fusion transcripts. Clin Cancer Res 14(20):6618–6624

    Article  PubMed  CAS  Google Scholar 

  108. Fukuyoshi Y, Inoue H, Kita Y, Utsunomiya T, Ishida T, Mori M (2008) EML4–ALK fusion transcript is not found in gastrointestinal and breast cancers. Br J Cancer 98(9):1536–1539

    Article  PubMed  CAS  Google Scholar 

  109. Perner S, Wagner PL, Demichelis F, Mehra R, Lafargue CJ, Moss BJ et al (2008) EML4–ALK fusion lung cancer: a rare acquired event. Neoplasia 10(3):298–302

    PubMed  CAS  Google Scholar 

  110. Takahashi T, Sonobe M, Kobayashi M, Yoshizawa A, Menju T, Nakayama E et al (2010) Clinicopathologic features of non-small-cell lung cancer with EML4–ALK fusion gene. Ann Surg Oncol 17(3):889–897

    Article  PubMed  Google Scholar 

  111. Wong DW, Leung EL, Wong SK, Tin VP, Sihoe AD, Cheng LC et al (2011) A novel KIF5B–ALK variant in nonsmall cell lung cancer. Cancer 117(12):2709–2718

    Article  PubMed  CAS  Google Scholar 

  112. Hernandez L, Bea S, Bellosillo B, Pinyol M, Falini B, Carbone A et al (2002) Diversity of genomic breakpoints in TFG–ALK translocations in anaplastic large cell lymphomas: identification of a new TFG–ALK(XL) chimeric gene with transforming activity. Am J Pathol 160(4):1487–1494

    Article  PubMed  CAS  Google Scholar 

  113. Drexler HG, Gignac SM, von Wasielewski R, Werner M, Dirks WG (2000) Pathobiology of NPM–ALK and variant fusion genes in anaplastic large cell lymphoma and other lymphomas. Leukemia 14(9):1533–1559

    Google Scholar 

  114. Caren H, Abel F, Kogner P, Martinsson T (2008) High incidence of DNA mutations and gene amplifications of the ALK gene in advanced sporadic neuroblastoma tumours. Biochem J 416(2):153–159

    Article  PubMed  CAS  Google Scholar 

  115. Murugan AK, **ng M (2011) Anaplastic thyroid cancers harbor novel oncogenic mutations of the ALK gene. Cancer Res 71(13):4403–4411

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Supported in part by NIH/NCI, RO1 5R01CA100750-09, 5R01CA125541-05, Respiratory Health Association of Metropolitan Chicago, Geleerd Family Foundation (RS), the Elise Anderson Neuroblastoma Research Foundation (SLC), the Children’s Neuroblastoma Cancer Foundation (SLC), and Little Heroes Cancer Research Foundation (SLC).

Conflict of interest

None

Author information

Authors and Affiliations

  1. Department of Pediatrics, University of Chicago, Chicago, IL, USA

    Andres Morales La Madrid & Susan L. Cohn

  2. Department of Medicine, University of Chicago, 5841 S. Maryland Avenue, MC 2115, Chicago, IL, 60637, USA

    Nicholas Campbell, Sonali Smith & Ravi Salgia

Authors
  1. Andres Morales La Madrid
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nicholas Campbell
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sonali Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Susan L. Cohn
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ravi Salgia
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ravi Salgia.

Rights and permissions

Reprints and permissions

About this article

Cite this article

La Madrid, A.M., Campbell, N., Smith, S. et al. Targeting ALK: a promising strategy for the treatment of non-small cell lung cancer, non-Hodgkin’s lymphoma, and neuroblastoma. Targ Oncol 7, 199–210 (2012). https://doi.org/10.1007/s11523-012-0227-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11523-012-0227-8

Keywords

Search

Navigation