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Resistance to ALK Inhibitors

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Resistance to Tyrosine Kinase Inhibitors

Part of the book series: Resistance to Targeted Anti-Cancer Therapeutics ((RTACT))

Abstract

The discovery of specific driver genetic alterations has led to the development of more tailored approaches for advanced human malignancies, moving short steps forward in the cure of these lethal diseases. Among them, rearrangements of the anaplastic lymphoma kinase (ALK) gene are key drivers in the carcinogenesis of a portion of anaplastic large cell lymphomas (ALCL) and non-small cell lung cancer (NSCLC). Many molecules targeting these specific rearrangements have been developed in preclinical models and clinical studies. Among these, crizotinib, an oral small-molecule tyrosine kinase inhibitor targeting ALK, MET, and ROS1 tyrosine kinases demonstrated a significant clinical activity in patients with ALK-positive tumors and, thus, achieved the US Food and Drug Administration (FDA) approval for the treatment of advanced NSCLC harboring ALK-rearrangements. Despite initially responses in most patients, acquired resistance to crizotinib arises unavoidably often within the first year of treatment. To overcome the acquired resistance more potent ALK inhibitors have been developed and tested in clinical trials with encouraging activity results. In this review, we discuss new findings about molecular mechanisms of crizotinib resistance and novel therapeutic strategies to address crizotinib resistance.

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Abbreviations

AKT:

V-Akt murine thymoma viral oncogene homolog

ALCL:

Anaplastic large cell lymphomas

ALK:

Anaplastic lymphoma kinase

BBB:

Blood-brain barrier

CNS:

Central nervous system

EGFR:

Epidermal growth factor receptor

EML4:

Echinoderm microtubule-associated protein-like 4

FDA:

Food and Drug Administration

HSP-90:

Heat shock protein 90 kDa

IGFR1:

Insulin-like growth factor receptor 1

IMFT:

Inflammatory myofibroblastic tumors

KIF5B:

Kinesin family member 5B

KIT:

V-Kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog

KRAS:

Kirsten rat sarcoma viral oncogene homolog

MET:

Met proto-oncogene tyrosine kinase

MTD:

Maximum tolerated dose

mTOR:

Mammalian target of rapamycin

NSCLC:

Non-small cell lung cancers

PFS:

Progression free survival

PI3K:

Phosphatidylinositol-4,5-bisphosphate 3-kinase

ROS1:

ROS proto-oncogene 1 receptor tyrosine kinase

RR:

Overall response rate

TFG:

Transforming growth factor

TKI:

Tyrosine kinase inhibitor

TRK:

Receptor tyrosine kinase

References

  1. Melisi D, et al. Rationale and clinical use of multitargeting anticancer agents. Curr Opin Pharmacol. 2013;13(4):536–42.

    Article  CAS  PubMed  Google Scholar 

  2. Shaw AT, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013;368(25):2385–94.

    Article  CAS  PubMed  Google Scholar 

  3. Mosse YP, et al. Safety and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma: a Children’s Oncology Group phase 1 consortium study. Lancet Oncol. 2013;14(6):472–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Solomon BJ, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. PROFILE 1014 Investigators. N Engl J Med. 2014;371(23):2167–77.

    Google Scholar 

  5. Morris SW, et al. ALK, the chromosome 2 gene locus altered by the t(2;5) in non-Hodgkin’s lymphoma, encodes a novel neural receptor tyrosine kinase that is highly related to leukocyte tyrosine kinase (LTK). Oncogene. 1997;14(18):2175–88.

    Article  CAS  PubMed  Google Scholar 

  6. Iwahara T, et al. Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system. Oncogene. 1997;14(4):439–49.

    Article  CAS  PubMed  Google Scholar 

  7. Souttou B, et al. Activation of anaplastic lymphoma kinase receptor tyrosine kinase induces neuronal differentiation through the mitogen-activated protein kinase pathway. J Biol Chem. 2001;276(12):9526–31.

    Article  CAS  PubMed  Google Scholar 

  8. Morris SW, et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. Science. 1994;263(5151):1281–4.

    Article  CAS  PubMed  Google Scholar 

  9. Griffin CA, et al. Recurrent involvement of 2p23 in inflammatory myofibroblastic tumors. Cancer Res. 1999;59(12):2776–80.

    CAS  PubMed  Google Scholar 

  10. Chiarle R, et al. The anaplastic lymphoma kinase in the pathogenesis of cancer. Nat Rev Cancer. 2008;8(1):11–23.

    Article  CAS  PubMed  Google Scholar 

  11. Lawrence B, et al. TPM3-ALK and TPM4-ALK oncogenes in inflammatory myofibroblastic tumors. Am J Pathol. 2000;157(2):377–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lamant L, et al. Expression of the ALK tyrosine kinase gene in neuroblastoma. Am J Pathol. 2000;156(5):1711–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Mano H, et al. Non-solid oncogenes in solid tumors: EML4-ALK fusion genes in lung cancer. Cancer Sci. 2008;99(12):2349–55.

    Google Scholar 

  14. Mano H, et al. EML4-ALK fusion in lung. Am J Pathol. 2010;176(3):1552–3. author reply 1553-4.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Soda M, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448(7153):561–6.

    Article  CAS  PubMed  Google Scholar 

  16. Barreca A, et al. Anaplastic lymphoma kinase in human cancer. J Mol Endocrinol. 2011;47(1):R11–23.

    Article  CAS  PubMed  Google Scholar 

  17. Zito Marino F, et al. Correction: intratumor heterogeneity of ALK-rearrangements and homogeneity of EGFR-mutations in mixed lung adenocarcinoma. PLoS One. 2015;10(10), e0141521.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Iwama E, et al. Development of anaplastic lymphoma kinase (ALK) inhibitors and molecular diagnosis in ALK rearrangement-positive lung cancer. Onco Targets Ther. 2014;7:375–85.

    PubMed  PubMed Central  Google Scholar 

  19. Huang Q, et al. Design of potent and selective inhibitors to overcome clinical anaplastic lymphoma kinase mutations resistant to crizotinib. J Med Chem. 2014;57(4):1170–87.

    Article  CAS  PubMed  Google Scholar 

  20. Esfahani K, et al. A systemic review of resistance mechanisms and ongoing clinical trials in ALK-rearranged non-small cell lung cancer. Front Oncol. 2014;4:174.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Kwak EL, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010;363(18):1693–703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Horn L, et al. EML4-ALK: honing in on a new target in non-small-cell lung cancer. J Clin Oncol. 2009;27(26):4232–5.

    Article  CAS  PubMed  Google Scholar 

  23. Solomon BJ, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014;371(23):2167–77.

    Article  PubMed  Google Scholar 

  24. Daniel B. et al. Clinical experience with crizotinib in patients with advanced ALK-rearranged non-small cell lung cancer and brain metastases. J Clin Oncol. 2015;33(17):1881–1888.

    Google Scholar 

  25. Solomon BJ, et al. Overall and intracranial (ic) efficacy results and time to symptom deterioration in profile 1014: 1st-line crizotinib vs pemetrexed − platinum chemotherapy (ppc) in patients (pts) with advanced alk-positive non-squamous non-small cell lung cancer (NSCLC). Ann Oncol. 2014;25(4):iv427.

    Google Scholar 

  26. Otterson M, et al. Clinical characteristics of ALK+ NSCLC patients (pts) treated with crizotinib beyond disease progression (PD): potential implications for management. Clin Oncol. 2012;30:7600.

    Google Scholar 

  27. Takeda M, et al. Clinical impact of continued crizotinib administration after isolated central nervous system progression in patients with lung cancer positive for ALK rearrangement. J Thorac Oncol. 2013;8(5):654–7.

    Article  CAS  PubMed  Google Scholar 

  28. Leduc C, 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(10):2092.

    Article  CAS  PubMed  Google Scholar 

  29. Chun SG, et al. Isolated central nervous system progression on Crizotinib: an Achilles heel of non-small cell lung cancer with EML4-ALK translocation? Cancer Biol Ther. 2012;13(14):1376–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Marsilje TH, et al. Synthesis, structure-activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulf onyl)phenyl)pyrimidine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials. J Med Chem. 2013;56(14):5675–90.

    Article  CAS  PubMed  Google Scholar 

  31. Costa DB, et al. CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib. J Clin Oncol. 2011;29(15):e443–5.

    Article  PubMed  Google Scholar 

  32. Ardini E, et al. Characterization of NMS-E628, a small molecule inhibitor of anaplastic lymphoma kinase with antitumor efficacy in ALK-dependent lymphoma and non-small cell lung cancer models. Mol Cancer There. 2009;8:A243.

    Google Scholar 

  33. Katayama R, et al. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers. Sci Transl Med. 2012;4(120):120ra17.

    Google Scholar 

  34. Friboulet L, et al. The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer. Cancer Discov. 2014;4(6):662–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ceccon M, et al. Crizotinib-resistant NPM-ALK mutants confer differential sensitivity to unrelated Alk inhibitors. Mol Cancer Res. 2013;11(2):122–32.

    Article  CAS  PubMed  Google Scholar 

  36. Heuckmann JM, 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 

  37. Sakamoto H, et al. CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant. Cancer Cell. 2011;19(5):679–90.

    Article  CAS  PubMed  Google Scholar 

  38. Shaw AT, et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med. 2014;370(13):1189–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Seto T, et al. CH5424802 (RO5424802) 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(7):590–8.

    Article  CAS  PubMed  Google Scholar 

  40. Ardini E, et al. In vitro and in vivo activity of NMS-E628 against ALK mutations resistant to Xalkori [EORTC-NCIAACR]. Mol Cancer Ther. 2011;10(11):A232.

    Google Scholar 

  41. Doebele RC, et al. Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res. 2012;18(5):1472–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Moore NF, et al. Molecular rationale for the use of PI3K/AKT/mTOR pathway inhibitors in combination with crizotinib in ALK-mutated neuroblastoma. Oncotarget. 2014;5(18):8737–49.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Ji C, et al. Induction of autophagy contributes to crizotinib resistance in ALK-positive lung cancer. Cancer Biol Ther. 2014;15(5):570–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Cheng Y, et al. MK-2206, a novel allosteric inhibitor of Akt, synergizes with gefitinib against malignant glioma via modulating both autophagy and apoptosis. Mol Cancer Ther. 2012;11(1):154–64.

    Article  CAS  PubMed  Google Scholar 

  45. Maillet D, et al. Ineffectiveness of crizotinib on brain metastases in two cases of lung adenocarcinoma with EML4-ALK rearrangement. J Thorac Oncol. 2013;8(4):e30–1.

    Article  PubMed  Google Scholar 

  46. Thomas RK, et al. Overcoming drug resistance in ALK-rearranged lung cancer. N Engl J Med. 2014;370(13):1250–1.

    Google Scholar 

  47. Leora H, et al. A phase I trial of X-396, a novel ALK inhibitor in patients with advanced solid tumors. J Clin Oncol. 2014;32:abstr 8030.

    Google Scholar 

  48. Ignatius Ou SH, et al. Next-generation sequencing reveals a Novel NSCLC ALK F1174V mutation and confirms ALK G1202R mutation confers high-level resistance to alectinib (CH5424802/RO5424802) in ALK-rearranged NSCLC patients who progressed on crizotinib. J Thorac Oncol. 2014;9(4):549–53.

    Article  CAS  PubMed  Google Scholar 

  49. Steuer CE, et al. Ramalingam SS. ALK-positive non-small cell lung cancer: mechanisms of resistance and emerging treatment options. Cancer. 2014;120(16):2392–402.

    Google Scholar 

  50. Koivunen JP, et al. EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin Cancer Res. 2008;14(13):4275–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Chen Z, et al. Inhibition of ALK, PI3K/MEK, and HSP90 in murine lung adenocarcinoma induced by EML4-ALK fusion oncogene. Cancer Res. 2010;70(23):9827–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Walker DP, et al. Trifluoromethylpyrimidine-based inhibitors of proline-rich tyrosine kinase 2 (PYK2): structure-activity relationships and strategies for the elimination of reactive metabolite formation. Bioorg Med Chem Lett. 2008;18(23):6071–7.

    Article  CAS  PubMed  Google Scholar 

  53. Zou HY. PF-06463922, a novel ROS1/ALK inhibitor, demonstrates sub-nanomolar potency against oncogenic ROS1 fusions and capable of blocking the resistant ROS1 G2032R mutant in preclinical tumor models. In: AACR-NCI-EORTC international conference on molecular targets and cancer therapeutics. Mol Cancer Ther. 2013;12:A277–A277.

    Google Scholar 

  54. Gainor JF, et al. Novel targets in non-small cell lung cancer: ROS1 and RET fusions. Oncologist. 2013;18(7):865–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Bergethon K, et al. ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol. 2012;30(8):863–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. De Braud F, et al. Phase I open label dose escalation study of RXDX101, an oral pan-trk, ROS1, and ALK inhibitor, in patients with advanced solid tumors with relevant molecular alterations. J Clin Oncol. 2014;32(5):2502.

    Google Scholar 

  57. Lovly CM, et al. Insights into ALK-driven cancers revealed through development of novel ALK tyrosine kinase inhibitors. Cancer Res. 2011;71(14):4920–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Mori M, et al. The selective anaplastic lymphoma receptor tyrosine kinase inhibitor ASP3026 induces tumor regression and prolongs survival in non-small cell lung cancer model mice. Mol Cancer Ther. 2014;13(2):329–40.

    Article  CAS  PubMed  Google Scholar 

  59. Patnaik A, et al. Pharmacokinetics and safety of an oral ALK inhibitor, ASP3026, observed in a phase I dose escalation trial. J Clin Oncol. 2013;31.2602.

    Google Scholar 

  60. Katayama R, et al. Two novel ALK mutations mediate acquired resistance to the next-generation ALK inhibitor alectinib. Clin Cancer Res. 2014;20(22):5686–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Katayama R, et al. Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK. Proc Natl Acad Sci U S A. 2011;108(18):7535–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Normant E, et al. The Hsp90 inhibitor IPI-504 rapidly lowers EML4-ALK levels and induces tumor regression in ALK-driven NSCLC models. Oncogene. 2011;30(22):2581–6.

    Article  CAS  PubMed  Google Scholar 

  63. Sequist LV, et al. Activity of IPI-504, a novel heat-shock protein 90 inhibitor, in patients with molecularly defined non-small-cell lung cancer. J Clin Oncol. 2010;28(33):4953–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Socinski MA, et al. A multicenter phase II study of ganetespib monotherapy in patients with genotypically defined advanced non-small cell lung cancer. Clin Cancer Res. 2013;19(11):3068–77.

    Article  CAS  PubMed  Google Scholar 

  65. Felip E, et al. Phase II activity of the Hsp90 inhibitor AUY922 in patients with ALK-rearranged (ALK) or EGFRmutated advanced non-small cell lung cancer. Ann Oncol. 2012;23:ix152–ix174.

    Google Scholar 

  66. Beckman RA, et al. Impact of genetic dynamics and single-cell heterogeneity on development of nonstandard personalized medicine strategies for cancer. Proc Natl Acad Sci U S A. 2012;109:14586–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Sang J, et al. Targeted inhibition of the molecular chaperone Hsp90 overcomes ALK inhibitor resistance in non-small cell lung cancer. Cancer Discov. 2013;3(4):430–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Gainor JF, et al. The central nervous system as a sanctuary site in ALK-positive non-small-cell lung cancer. J Thorac Oncol. 2013;8(12):1570–3.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgement

This work was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC) Start-Up no. 10129, and 5 per mille no. 10016 to DM, and by the AIRC grants IG 11930, 5 per mille 12182, 12214, and PRIN no. 2009X23L78_005 to GT.

Disclosure

The authors have declared no conflicts of interest.

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Authors and Affiliations

  1. Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy

    Francesca Simionato, Giampaolo Tortora & Davide Melisi

  2. Comprehensive Cancer Center, Azienda Ospedaliera Universitaria Integrata, Verona, Italy

    Giampaolo Tortora

  3. Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, Università degli studi di Verona, Verona, Italy

    Francesca Simionato, Carmine Carbone & Davide Melisi

  4. Laboratory of Oncology and Molecular Therapy, Department of Medicine, Università degli studi di Verona, Verona, Italy

    Carmine Carbone, Giampaolo Tortora & Davide Melisi

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  1. Francesca Simionato
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  2. Carmine Carbone
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  3. Giampaolo Tortora
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  4. Davide Melisi
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Correspondence to Davide Melisi .

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  1. Pisa University Hospital, Pisa, Italy

    Daniele Focosi

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Simionato, F., Carbone, C., Tortora, G., Melisi, D. (2016). Resistance to ALK Inhibitors. In: Focosi, D. (eds) Resistance to Tyrosine Kinase Inhibitors. Resistance to Targeted Anti-Cancer Therapeutics. Springer, Cham. https://doi.org/10.1007/978-3-319-46091-8_5

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