Skip to main content

Advertisement

SpringerLink
Log in

Treating patients with ALK-rearranged non-small-cell lung cancer: mechanisms of resistance and strategies to overcome it

  • Review Article
  • Published:
Clinical and Translational Oncology Aims and scope Submit manuscript

Abstract

Anaplastic lymphoma kinase (ALK) rearrangement is detected in 3–7% of patients with non-small-cell lung cancer. Crizotinib is an ALK inhibitor, which was approved in 2011 for the treatment of ALK-positive lung cancer. Despite the initial enthusiasm, most of the patients develop resistance within the first year of treatment. The main mechanisms are secondary mutations and bypass track activation. Moreover, crizotinib has low penetration into the central nervous system. The need to overcome these limitations has led to the development of second-generation inhibitors that have better effectiveness against crizotinib-resistant mutations and brain metastases. Ceritinib and alectinib are the only approved drugs of this group. Many ongoing trials try to define the most appropriate agent for the treatment of ALK-positive lung cancer depending on the responsible mechanism. This review focuses on the current data regarding the potential mechanisms of resistance to ALK inhibitors and the strategies to overcome it.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Siegel R, Miller K, Jemal A. Cancer statistics. CA Cancer J Clin. 2016;66:7–30.

    Article  PubMed  Google Scholar 

  2. Siegel RL, Miller KD, Jemal A. Cancer statistics 2016. Ca Cancer J Clin. 2016;66:7–30.

  3. Ettinger D, Wood D, Akerley W, Bazhenova L, Borghaei H, Camidge DR et al. Non-small-cell lung cancer, Version 6.2015. Featured updates to the NCCN guidelines. JNCCN. 2015;13(5):517–21.

  4. Candarella S, Johnson B. The impact of genomic changes on treatment of lung cancer. Am J Respir Crit Care Med. 2013;188(7):770–5.

    Article  Google Scholar 

  5. Awad M, Shaw AT. ALK inhibitors in non-small-cell lung cancer: crizotinib and beyond. Clin Adv Hematol Oncol. 2014;12(7):429–39.

    PubMed  PubMed Central  Google Scholar 

  6. Sullivan I, Planchard D. Treatment modalities for advanced ALK-rearranged non-small-cell lung cancer. Future Oncol. 2016. doi:10.2217/fon.16.15.

    Google Scholar 

  7. Van der Wekken AJ, Saber A, Hiltermann TJN, Kok K, Van den Berg A, Groen HJM. Resistance mechanisms after tyrosine kinase inhibitors afatinib and crizotinib in non-small cell lung cancer, a review of the literature. Crit Rev Oncol/Hematol. 2016. doi:10.1016/j.critrevonc.2016.01.024.

    Google Scholar 

  8. Lovly C, Shaw AT. Molecular pathways: resistance to kinase inhibitors and implications for therapeutic strategies. Clin Cancer Res. 2014;20(9):2249–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Bayliss R, Choi J, Fennell DA, Fry AM, Richards MW. Molecular mechanisms that underpin EML4-ALK driven cancers and their response to targeted drugs. Cell. 2016;73:1209–24.

    CAS  Google Scholar 

  10. Morris SW, Kirstein MN, Valentine MB, Dittmer KG, Shapiro DN, Saltman DL, et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma. Science. 1994;263:1281–4.

    Article  CAS  PubMed  Google Scholar 

  11. Shaw AT, Solomon B. Targeting anaplastic lymphoma kinase in lung cancer. Clin Cancer Res. 2011. doi:10.1158/1078-0432.

    PubMed Central  Google Scholar 

  12. Webb T, Slavish J, George RE, Look AT, Xue L, Jiang Q, et al. Anaplastic lymphoma kinase: role in cancer pathogenesis and small-molecule inhibitor development for therapy. Expert Rev Anticancer Ther. 2009;9(3):331–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448:561–6.

    Article  CAS  PubMed  Google Scholar 

  14. Gerber D, Minna J. ALK inhibition for non-small-cell lung cancer: from discovery to therapy in record time. Cancer Cell. 2010. doi:10.1016/j.ccr.2010.11.033.

    PubMed  PubMed Central  Google Scholar 

  15. Shaw AT, Yeap BY, Mino-Kenudson M, Digumarthy SR, Costa DB, Heist RS, et al. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol. 2009;27:4247–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lindeman NI, Cagle PT, Beasley MB, Chitale DA, Dacic S, Giaccone G, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. J Thorac Oncol. 2013;8:823–59.

  17. Toyokawa G, Seto T, Takenoyama M, Ichinose Y. Insights into brain metastasis in patients with ALK+ lung cancer: is the brain truly a sanctuary? Cancer Metastasis Rev. 2015;34:797–805.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Rangachari D, Yamaguchi N, VanderLaan PA, Folch E, Mahadevan A, Floyd SR, et al. Brain metastases in patients with EGFR-mutated or ALK-rearranged non-small cell lung cancers. Lung Cancer. 2015;88(1):108–11.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Christensen JG, Zou HY, Arango ME, Li Q, Lee JH, McDonnell SR, et al. Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma. Mol Cancer Ther. 2007;6(12):3314–22.

    Article  CAS  PubMed  Google Scholar 

  20. Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B, Maki RG, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010;363:1693–703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Camidge DR, Bang YJ, Kwak EL, Iafrate AJ, Varella-Garcia M, Fox SB, et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase I study. Lancet Oncol. 2012;13(10):1011–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Crino L, Kim DW, Riely GJ, Janne PA, Blackhall FH, Camidge DR, et al. Initial phase 2 results with crizotinib in advanced ALK-positive non-small-cell lung cancer (NSCLC): PROFILE 1005. J Clin Oncol. 2011;29:7514.

    Article  Google Scholar 

  23. Ou SHI, Bartlett CH, Mino-Kenudson M, Cui J, Iafrate AJ. Crizotinib for the treatment of ALK-rearranged non-small-cell lung cancer: a success story to usher in the second decade of molecular targeted therapy in oncology. Oncologist. 2012;17:1351–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Shaw AT, Kim DW, Nakagawa K, Seto T, Crino L, Ahn MJ, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013;368:2385–94.

    Article  CAS  PubMed  Google Scholar 

  25. Solomon B, Mok T, Kim DW, Wu YL, Nakagawa K, Mekhail T, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014;371:2167–77.

    Article  PubMed  Google Scholar 

  26. Clinicaltrials.gov.

  27. Morgensztern D, Campo MJ, Dahlberg SE, Doebele RC, Garon E, Gerber DE, et al. Molecularly targeted therapies in non-small-cell lung cancer annual update 2014. J Thorac Oncol. 2015;10:S1–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ye M, Zhang X, Li N, Zhang Y, Jing P, Chang N, et al. ALK and ROS1 as targeted therapy paradigms and clinical implications to overcome crizotinib resistance. Oncotarget. 2016;7(11):12289–304.

    PubMed  PubMed Central  Google Scholar 

  29. Choi YL, Soda M, Yamashita Y, Toshihide U, Takashima J, Nakajima T, et al. EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. N Engl J Med. 2010;363:1734–9.

    Article  CAS  PubMed  Google Scholar 

  30. Camidge DR, Doebele RC. Treating ALK-positive lung cancer- early success and future challenges. Nat Rev Clin Oncol. 2012;9(5):267–77.

    Article  Google Scholar 

  31. Toyokawa G, Seto T. Updated evidence on the mechanisms of resistance to ALK inhibitors and strategies to overcome such resistance: clinical and preclinical data. Oncol Res Treat. 2015;38:291–8.

    Article  CAS  PubMed  Google Scholar 

  32. Sullivan I, Planchard D. ALK inhibitors in non-small-cell lung cancer: the latest evidence and developments. Ther Adv Med Oncol. 2016;8(1):32–47.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Costa DB, Kobayashi S, Pandya SS, Yeo WL, Shen Z, Tan W, et al. CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib. J Clin Oncol. 2011;29:e443–5.

    Article  PubMed  Google Scholar 

  34. Rolfo C, Passiglia F, Castiglia M, Raez LE, Germonpre P, Gil-Bazo I, et al. ALK and crizotinib: after the honeymoon…what else? Resistance mechanisms and new therapies to overcome it. Transl Lung Cancer Res. 2014;3(4):250–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Steuer C, Ramalingam S. ALK positive non-small cell lung cancer, mechanisms of resistance and emerging treatment options. Cancer. 2014;120:2392–402.

    Article  CAS  PubMed  Google Scholar 

  36. Sasaki T, Koivunen J, Ogino A, Yanagita M, Nikiforow S, Zheng W, et al. A novel ALK secondary mutation and EGFR signaling cause resistance to ALK kinase inhibitors. Cancer Res. 2011;71:6051–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Sasaki T, Okuda K, Zheng W, Butrynski J, Capelletti M, Wang L, et al. The neuroblastoma associated F1174L mutation causes resistance to an ALK kinase inhibitor in ALK translocated cancers. Am Assoc Cancer Res. 2010. doi:10.1158/0008-5472.CAN-10-2956.

    Google Scholar 

  40. Heuckmann JM, Holzel M, Sos ML, Heynck S, Balke-Want H, Koker M, et al. ALK mutations conferring differential resistance to structurally diverse ALK inhibitors. Clin Cancer Res. 2011;17(23):7394–401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Maione P, Sacco PC, Sgambato A, Casaluce F, Rossi A, Gridelli C. overcoming resistance to targeted therapies in NSCLC: current approaches and clinical application. Ther Adv Med Oncol. 2015;7(5):263–73.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Isozaki H, Takigawa N, Kiura K. Mechanisms of acquired resistance to ALK inhibitors and the rationale for treating ALK-positive lung cancer. Cancers. 2015;7:763–83.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Yamaguchi N, Lucena-Araujo AR, Nakayama S, Figueiredo-Pontes L, Gonzalez DA, Yasuda H, et al. Dual ALK and EGFR inhibition targets a mechanism of acquired resistance to the TKI crizotinib in ALK rearranged lung cancer. Lung Cancer. 2014;83(1):37–43.

    Article  PubMed  Google Scholar 

  44. Awad M, Katayama R, McTigue M, Liu W, Deng YL, Brooun A, et al. Acquired resistance to crizotinib from a mutation in CD74-ROS1. N Engl J Med. 2013. doi:10.1056/NEJMoa1215530.

    PubMed Central  Google Scholar 

  45. Tanizaki J, Okamoto I, Okabe T. Activation of HER family signaling as a mechanism of acquired resistance to ALK inhibitors in EML4-ALK-positive non-small cell lung cancer. Clin Cancer Res. 2012. doi:10.1158/1078-0432.

    PubMed  Google Scholar 

  46. Cha YJ, Cho BC, Kim HR, Lee HJ, Shim HS. A case of ALK-rearranged adenocarcinoma with small cell carcinoma-like transformation and resistance to crizotinib. J Thorac Oncol. 2015;11(5):e55–8.

    Article  PubMed  Google Scholar 

  47. Nix N, Brown K. Ceritinib for ALK-rearrangement-positive non-small-cell lung cancer. J Adv Pract Oncol. 2015;6:156–60.

    PubMed  PubMed Central  Google Scholar 

  48. Raedler L. Zykadia (ceritinib) approved for patients with crizotinib-resistant ALK-positive non-small cell lung cancer. Am Health Drug Benef. 2015;8:163–6.

    Google Scholar 

  49. Khozin S, Blumenthal GM, Zhang L, Tang S, Brower M, Fox E, et al. FDA approval: ceritinib for the treatment of metastatic anaplastic lymphoma kinase-positive non-small cell lung cancer. Am Assoc Cancer Res. 2015. doi:10.1158/1078-0432.CCR-14-3157.

    Google Scholar 

  50. Shaw AT, Kim DW, Mehra R, Tan DSW, Felip E, Chow LQM, et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med. 2014;370:1189–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Kim DW, Mehra R, Tan DSW, Felip E, Chow LQM, Camidge R, et al. Activity and safety of ceritinib in patients with ALK-rearranged non-small-cell lung cancer (ASCEND-1): updated results from the multicentre, open-label, phase 1 trial. Lancet Oncol. 2016;17(4):452–63.

    Article  Google Scholar 

  52. Mok T, Spiegel D, Felip E, deMarinis F, Ahn MJ, Groen HJM, et al. ASCEND-2: a single-arm, open-label, multicenter phase II study of ceritinib in adult patients with ALK-rearranged(ALK+) non-small cell lung cancer previously treated with chemotherapy and crizotinib. J Clin Oncol. 2015;33:8059.

    Google Scholar 

  53. Felip E, Orlov S, Park K, Yu CJ, Tsai CM, Nishio M, et al. ASCEND-3: a single-arm, open-label, multicenter phase II study of ceritinib ALKi-naïve adult patients with ALK-rearranged (ALK+) non-small cell lung cancer. J Clin Oncol. 2015;33:8060.

    Google Scholar 

  54. El-Osta H, Shackelford R. Personalized treatment options for ALK-positive metastatic non-small-cell lung cancer: potential role for ceritinib. Pharmacogen Pers Med. 2015;8:145–54.

    Google Scholar 

  55. Friboulet L, Li N, Katayama R, Lee CC, Gainor JF, Crystal AS, et al. The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small-cell lung cancer. Cancer Discov. 2014;4:662–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Toyokawa G, Inamasu E, Shimamatsu S, Yoshida T, Nosaki K, Hirai F, et al. Identification of a novel ALK G1123S mutation in a patient with ALK rearranged NSCLC exhibiting resistance to ceritinib. J Thorac Oncol. 2015;10(7):55–7.

    Article  Google Scholar 

  57. Dong X, Fernandez-Salas E, Li E, Wang S. Elucidation of resistance mechanisms to second-generation ALK inhibitors alectinib and ceritinib in non-small-cell lung cancer cells. Neoplasia. 2016;18(3):162–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Katayama R, Sakashita T, Yanagitani N, Ninomiya H, Horiike A, Friboulet L, et al. P-glycoprotein mediates ceritinib resistance in anaplastic lymphoma kinase-rearranged non-small-cell lung cancer. EBioMedicine. 2016;3:54–66.

    Article  PubMed  Google Scholar 

  59. Iragavarapu C, Mustafa M, Akinleye A, Furqan M, Mittal V, Cang S, et al. Novel ALK inhibitors in clinical use and development. J Hematol Oncol. 2015;8:17.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Larkins E, Blumenthal GM, Chen H, He K, Agarwal R, Gieser G, et al. FDA approval: alectinib for the treatment of metastatic ALK positive non-small cell lung cancer following crizotinib. Clin Cancer Res. 2016. doi:10.1158/1078-0432.CCR-16-1293.

    PubMed  Google Scholar 

  61. Lovly C. Combating acquired resistance to tyrosine kinase inhibitors in lung cancer. Am Soc Clin Oncol Educ Book. 2015;e165–e173. doi:10.14694/EdBook_AM.2015.35.e165.

  62. Seto T, Kiura K, Nishio M, Nakagawa K, Maemondo M, Inoue A, et al. Alectinib for patients with ALK-rearranged advanced non-small-cell lung cancer (AF 001JP study): a single-arm, open-label, phase 1-2 study. Lancet Oncol. 2013;14:590–8.

    Article  CAS  PubMed  Google Scholar 

  63. Tamura T, Seto T, Nakagawa K, Maemondo M, Inoue A, Hida T, et al. Updated data of a phase 1-2 study (AF001JP) of alectinib, a CNS-penetrant, highly selective ALK inhibitor in ALK-rearranged advanced NSCLC. Radiat Oncol. 2014;90:S6.

    Google Scholar 

  64. Ou SHI, Ahn JS, De Petris L, Govindan R, Yang JCH, Hughes B, et al. Alectinib in crizotinib-refractory ALK-rearranged non-small-cell lung cancer: a phase II global study. J Clin Oncol. 2015;33:1–8.

  65. Shaw AT, Gandhi L, Gadgeel S, Riely GJ, Cetnar J, West H, et al. Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: a single-group, multicentre, phase 2 trial. Lancet Oncol. 2015;17(2):234–42.

    Article  Google Scholar 

  66. Katayama R, Friboulet L, Koike S, Lockerman EL, Khan TM, Gainor JF, et al. Two novel ALK mutations mediate acquired resistance to the next generation ALK inhibitor alectinib. Clin Cancer Res. 2014. doi:10.1158/1078-0432.CCR-14-1511.

    Google Scholar 

  67. Ou SH, Milliken JC, Azada MC, Miller VA, Ali SM, Klempner SJ. ALK, F1174V mutation confers sensitivity while ALK I1171 mutation confers resistance to alectinib. The importance of serial biopsy post progression. Lung Cancer. 2016;91:70–2.

    Article  PubMed  Google Scholar 

  68. Ou SHI, Azada M, Hsiang DJ, Herman JM, Kain TS, Siwak-Tapp C, et al. Next-generation sequencing reveals a novel NSCLC ALK F1174V mutation and confirms ALK G1202R mutation confers high-level resistance to Alectinib in ALK-rearranged NSCLC patients who progressed on crizotinib. J Thorac Oncol. 2014;9:549–53.

    Article  Google Scholar 

  69. Toyokawa G, Seto T, Takenoyama M, Ichinose Y. Crizotinib can overcome acquired resistance to CH5424802. Is amplification of the MET gene a key factor? J Thorac Oncol. 2014;9(3):e27–8.

    Article  Google Scholar 

  70. Isozaki H, Hotta K, Ichihara E, Takigawa N, Ohashi K, Kubo T, et al. Protocol design for the bench to bed trial in alectinib-refractory non-small-cell lung cancer patients harboring the EML4-ALK fusion gene (ALRIGHT/OLCSG1405). Clin Lung Cancer. 2016. doi:10.1016/j.cllc.2016.05.005.

    PubMed  Google Scholar 

  71. Fujita S, Masago K, Katakami N, Yatabe Y. Transformation to SCLC after treatment with the ALK inhibitor alectinib. J Thorac Oncol. 2016;11(6):e67–72.

    Article  PubMed  Google Scholar 

  72. Romanidou O, Landi L, Cappuzzo F, Califano R. Overcoming resistance to first/second generation EGFR TKIs and ALK inhibitors in oncogene-addicted advanced non-small cell lung cancer. Ther Adv Med Oncol. 2016;8:176–87.

  73. Ou SHI, Janne PA, Bartlett CH, Tang Y, Kim DW, Otterson GA, et al. Clinical benefit of continuing ALK inhibition with crizotinib beyond initial disease progression in patients with advanced ALK-positive NSCLC. Ann Oncol. 2014;25(2):415–22.

    Article  PubMed  Google Scholar 

  74. Peters S. Emerging options after progression during crizotinib therapy. J Clin Oncol. 2015. doi:10.1200/JCO.2015.65.1406.

    Google Scholar 

  75. Gadgeel SM, Gandhi L, Riely GJ, Chiappori AA, West HL, Azada MC, et al. Safety and activity of Alectinib against systemic disease and brain metastases in patients with Crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF 002JG): results from the dose finding portion of a phase 1–2 study. Lancet Oncol. 2014;15:1119–28.

    Article  CAS  PubMed  Google Scholar 

  76. Kim YH, Ozasa H, Nagai H, Sakamori Y, Yoshida H, Yagi Y, et al. High-dose crizotinib for brain metastases refractory to standard-dose crizotinib. J Thorac Oncol. 2013;8(9):85–6.

    Article  Google Scholar 

  77. Felip E, Crino L, Kim DW, Spigel DR, Nishio M, Mok T, et al. Whole body and intracranial efficacy of ceritinib in patients with crizotinib pretreated, ALK-rearranged non-small-cell lung cancer and baseline brain metastases. Results from ASCEND-1 and ASCEND-2 trials. J Thorac Oncol. 2016;11:S57–166.

    Google Scholar 

  78. Ou SH, Shaw AT, Govindan R, Socinski M, Camidge R, De Petris L, et al. Pooled analysis of CNS response to alectinib in two studies of pre-treated ALK+ NSCLC. 16th WCLC-IACLC. 2015.

  79. Gainor JF, Chi AS, Logan J, Hu R, Oh KS, Brastianos PK, et al. Alectinib dose escalation reinduces central nervous system responses in patients with anaplastic lymphoma kinase-positive NSCLC relapsing on standard dose alectinib. J Thorac Oncol. 2015;11(2):256–60.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Gainor J, Sherman CA, Willoughby K, Logan J, Kennedy E, Brastianos PK, et al. Alectinib salvages CNS relapses in ALK-positive lung cancer patients previously treated with crizotinib and ceritinib. J Thorac Oncol. 2015;10(2):232–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Tang SC, Nguyen LN, Sparidans RW, Wagenaar E, Beijnen JH, Shinkel AH. Increased oral availability and brain accumulation of the ALK inhibitor crizotinib by coadministration of the P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) inhibitor elacridar. Int J Cancer. 2014;134:1484–94.

    Article  PubMed  Google Scholar 

  82. Johung KL, Yeh N, Desai NB, Williams TM, Lautenshlaeger T, Arvold ND, et al. Extended survival and prognostic factors for patients with ALK-rearranged non-small-cell lung cancer and brain metastasis. J Clin Oncol. 2015;34(2):123–9.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Weickhardt AJ, Scheier B, Burke JM, Gan G, Lu X, Bunn PA, et al. Local ablative therapy of oligoprogessive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non-small-cell lung cancer. J Thorac Oncol. 2012;7(12):1807–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Squillace RM, Anjum R, Miller D, Vodala S, Moran L, Wang F, et al. AP 26113 possesses pan-inhibitory activity versus crizotinib-resistant ALK mutants and oncogenic ROS1 fusions. Cancer Res. 2013;73:5655.

    Article  Google Scholar 

  85. Wu J, Savooji J, Liu D. Second- and third-generation ALK inhibitors for non-small cell lung cancer. J Hematol Oncol. 2016;9:19.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Facchinetti F, Tiseo M, Di Maio M, Graziano P, Bria E, Rossi G, et al. Tackling ALK in non-small cell lung cancer: the role of novel inhibitors. Transl Lung Cancer Res. 2016;5(3):301–21.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Liao BC, Lin CC, Shih JY, Yang JCH. Treating patients with ALK-positive non-small-cell lung cancer: latest evidence and management strategy. Ther Adv Med Oncol. 2015;7(5):274–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Li T, LoRusso P, Maitland ML, Ou SHI, Bahceci E, Ball HA, et al. First-in-human, open-label dose escalation and dose expansion study of the safety, pharmacokinetics, and antitumor effects of an oral ALK inhibitor ASP3026 in patients with advanced solid tumors. J Hematol Oncol. 2016;9:23.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Reckamp KL, Infante JR, Blumenschein GR, Wakelee HA, Carter CA, Gockerman JP, et al. Phase I/II trial of X-396, a novel anaplastic lymphoma kinase inhibitor, in patients with ALK+ non-small-cell lung cancer. J Thorac Oncol. 2016;11(2):S36–7.

    Article  Google Scholar 

  90. Shaw AT, Friboulet L, Leshchiner I, Gainor JF, Bergqvist S, Brooun A, et al. Resensitization to crizotinib by the lorlatinib ALK resistance mutation L1198F. N Engl J Med. 2015. doi:10.1056/NEJMoa1508887.

    PubMed Central  Google Scholar 

  91. Wang W, Jiang X, Song Z, Zhang Y. Patients harboring EGFR mutation after primary resistance to crizotinib and response to EGFR-TKI. OncoTargets Ther. 2016;9:211–5.

    Article  Google Scholar 

  92. Lovly CM, Mc Donald NT, Chen H, Ortiz-Cuaran S, Heukamp LC, Yan Y, et al. Rationale for co-targeting IGF-1R and ALK in ALK fusion positive lung cancer. Nat Med. 2014;20(9):1027–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Tan DSW, Araujo A, Zhang J, Signorovitch J, Zhou ZY, Cai X, et al. Comparative efficacy of ceritinib and crizotinib as initial ALK-targeted therapies in previously treated advanced NSCLC: an adjusted comparison with external controls. J Thorac Oncol. 2016;11(9):1550–7.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. St. Savvas Regional Hospital for Cancer Treatment, 171 Alexandras Avenue, 11522, Athens, Greece

    M. Drizou

  2. Oncology Unit, Athens School of Medicine, Sotiria General Hospital, 152 Mesogion Avenue, 11527, Athens, Greece

    E. A. Kotteas & N. Syrigos

Authors
  1. M. Drizou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E. A. Kotteas
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. N. Syrigos
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E. A. Kotteas.

Ethics declarations

Research involving human participants and/or animals

This article does not contain any studies with human participants or animals performed by any of the authors.

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Drizou, M., Kotteas, E.A. & Syrigos, N. Treating patients with ALK-rearranged non-small-cell lung cancer: mechanisms of resistance and strategies to overcome it. Clin Transl Oncol 19, 658–666 (2017). https://doi.org/10.1007/s12094-016-1605-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12094-016-1605-y

Keywords

Search

Navigation