Abstract
Chromosomal rearrangement in the anaplastic lymphoma kinase (ALK) gene was identified as an oncogenic driver in non-small cell lung cancer (NSCLC) in 2007. A multi-targeted ALK/ROS1/MET inhibitor, crizotinib, targeting this activated tyrosine kinase has led to significant clinical benefit including tumor shrinkage and prolonged survival without disease progression and has been approved by US FDA since 2011 for the treatment of advanced ALK-rearranged NSCLC (Ou et al. Oncologist 17:1351–1375, 2012). Knowledge gained from treating ALK-rearranged NSCLC patients including the presenting clinicopathologic characteristics, methods of detecting ALK-rearranged NSCLC, pattern of relapse and acquired resistance mechanisms while on crizotinib, and the clinical activities of more potent ALK inhibitors has led us to a detailed and ever expanding knowledge of the ALK signaling pathway in lung cancer but also raising many more questions that remained to be answered in the future. This book chapter will provide a concise summary of the importance of ALK signaling pathway in lung cancer. Understanding the ALK signaling pathway in lung cancer will likely provide the roadmap to the management of major epithelial malignancies driven by receptor tyrosine kinase rearrangement.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Mitelman F, Johansson B, Mertens F (2004) Fusion genes and rearranged genes as a linear function of chromosome aberrations in cancer. Nat Genet 36:331–334
Soda M, Choi YL, Enomoto M et al (2007) Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448:561–566
Rikova K, Guo A, Zeng Q et al (2007) Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell 131:1190–1203
Soda M, Takada S, Takeuchi K et al (2008) A mouse model for EML4-ALK-positive lung cancer. Proc Natl Acad Sci U S A 105:19893–19897
Blume-Jensen P, Hunter T (2001) Oncogenic kinase signalling. Nature 411:355–365
Morris SW, Kirstein MN, Valentine MB et al (1994) Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma. Science 263:1281–1284
Chiarle R, Voena C, Ambrogio C et al (2008) The anaplastic lymphoma kinase in the pathogenesis of cancer. Nat Rev Cancer 8:11–23
Takezawa K, Okamoto I, Nishio K et al (2011) Role of ERK-BIM and STAT3-survivin signaling pathways in ALK inhibitor-induced apoptosis in EML4-ALK-positive lung cancer. Clin Cancer Res 17:2140–2148
Ou SH, Bartlett CH, Mino-Kenudson M et al (2012) 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 17:1351–1375
Li T, Maus MK, Desai SJ et al (2014) Large-scale screening and molecular characterization of EML4-ALK fusion variants in archival non-small-cell lung cancer tumor specimens using quantitative reverse transcription polymerase chain reaction assays. J Thorac Oncol 9:18–25
Fang DD, Zhang B, Gu Q et al (2014) HIP1-ALK, a novel ALK fusion variant that responds to crizotinib. J Thorac Oncol 9:285–294
Hong M, Kim RN, Song JY et al (2014) HIP1-ALK, a novel fusion protein identified in lung adenocarcinoma. J Thorac Oncol 9:419–422
Heuckmann JM, Balke-Want H, Malchers F et al (2012) Differential protein stability and ALK inhibitor sensitivity of EML4-ALK fusion variants. Clin Cancer Res 18:4682–4690
Shaw AT, Yeap BY, Mino-Kenudson M et al (2009) Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol 27:4247–4253
Kwak EL, Bang YJ, Camidge DR et al (2010) Anaplastic lymphoma kinase inhibition in non- small-cell lung cancer. N Engl J Med 363:1693–1703
Camidge DR, Bang YJ, Kwak EL et al (2012) Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol 13:1011–1019
Yoshida A, Tsuta K, Nakamura H et al (2011) Comprehensive histologic analysis of ALK- rearranged lung carcinomas. Am J Surg Pathol 35:1226–1234
Klempner SJ, Cohen DW, Costa DB (2011) ALK translocation in non-small cell lung cancer with adenocarcinoma and squamous cell carcinoma markers. J Thorac Oncol 6:1439–1440
Toyokawa G, Takenoyama M, Taguchi K et al (2013) An extremely rare case of small-cell lung cancer harboring variant 2 of the EML4-ALK fusion gene. Lung Cancer 81:487–490
Ou SH (2013) Lung cancer in never-smokers. Does smoking history matter in the era of molecular diagnostics and targeted therapy? J Clin Pathol 66:839–846
Doebele RC, Lu X, Sumey C et al (2012) Oncogene status predicts patterns of metastatic spread in treatment-naive nonsmall cell lung cancer. Cancer 118:4502–4511
Shaw AT, Kim DW, Nakagawa K et al (2013) Crizotinib versus chemotherapy in advanced ALK- positive lung cancer. N Engl J Med 368:2385–2394
Camidge DR, Kono SA, Lu X et al (2011) Anaplastic lymphoma kinase gene rearrangements in non-small cell lung cancer are associated with prolonged progression-free survival on pemetrexed. J Thorac Oncol 6:774–780
Shaw AT, Varghese AM, Solomon BJ et al (2013) Pemetrexed-based chemotherapy in patients with advanced, ALK-positive non-small cell lung cancer. Ann Oncol 24:59–66
Berge EM, Lu X, Maxson D, Barón AE et al (2013) Clinical benefit from pemetrexed before and after crizotinib exposure and from crizotinib before and after pemetrexed exposure in patients with anaplastic lymphoma kinase-positive non-small-cell lung cancer. Clin Lung Cancer 14:636–643
Lee JO, Kim TM, Lee SH et al (2011) Anaplastic lymphoma kinase translocation: a predictive biomarker of pemetrexed in patients with non-small cell lung cancer. J Thorac Oncol 6:1474–1480
Ou SHI, Soo RA, Kubo A et al (2014) Will the requirement by the US FDA to simultaneously co- develop companion diagnostics (CDx) delay the approval of receptor tyrosine kinase inhibitors for RTK-rearranged (ROS1-, RET-, AXL-, PDGFR-α-, NTRK1-) non-small cell lung cancer globally? Front Oncol. doi:10.3389/fonc.2014.00058
Paik JH, Choe G, Kim H et al (2011) Screening of anaplastic lymphoma kinase rearrangement by immunohistochemistry in non-small cell lung cancer: correlation with fluorescence in situ hybridization. J Thorac Oncol 6:466–472
Ying J, Guo L, Qiu T et al (2013) Diagnostic value of a novel fully automated immunochemistry assay for detection of ALK rearrangement in primary lung adenocarcinoma. Ann Oncol 24:2589–2593
Mino-Kenudson M, Chirieac LR, Law K et al (2010) A novel, highly sensitive antibody allows for the routine detection of ALK-rearranged lung adenocarcinomas by standard immunohistochemistry. Clin Cancer Res 16:1561–1571
Ou SH, Azada M, Hsiang D et al (2014) 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 9:549–553
Kim HR, Shim HS, Chung JH et al (2012) Distinct clinical features and outcomes in never- smokers with nonsmall cell lung cancer who harbor EGFR or KRAS mutations or ALK rearrangement. Cancer 118:729–739
Yang P, Kulig K, Boland JM et al (2012) Worse disease-free survival in never-smokers with ALK+ lung adenocarcinoma. J Thorac Oncol 7:90–97
Shaw AT, Yeap BY, Solomon BJ et al (2011) Effect of crizotinib on overall survival in advanced NSCLC harboring anaplastic lymphoma kinase gene rearrangement: a retrospective analysis. Lancet Oncol 11:1004–1012
Takeuchi K, Soda M, Togashi Y et al (2012) RET, ROS1 and ALK fusions in lung cancer. Nat Med 18:378–381
Ou SH, Janne PA, Bartlett CH et al (2014) Clinical benefit of continuing ALK inhibition with crizotinib beyond initial disease progression in patients with advanced ALK-positive NSCLC. Ann Oncol 25:415–422
Zou HY, Li Q, Lee JH et al (2007) An orally available small-molecule inhibitor of c-Met, PF- 2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms. Cancer Res 67:4408–4417
Christensen JG, Zou HY, Arango ME et al (2007) 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 6:3314–3322
Gan GN, Weickhardt AJ, Scheier B et al (2014) Stereotactic radiation therapy can safely and durably control sites of extra-central nervous system oligoprogressive disease in anaplastic lymphoma kinase-positive lung cancer patients receiving crizotinib. Int J Radiat Oncol Biol Phys 88:892–898
Pop O, Pirvu A, Toffart AC et al (2012) Disease flare after treatment discontinuation in a patient with EML4-ALK lung cancer and acquired resistance to crizotinib. J Thorac Oncol 7:e1–e2
Costa DB, Kobayashi S, Pandya SS et al (2011) CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib. J Clin Oncol 29:e443–e445
Choi YL, Soda M, Yamashita Y et al (2010) EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. N Engl J Med 363:1734–1739
Doebele RC, Pilling AB, Aisner DL et al (2012) Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res 18:1472–1482
Katayama R, Shaw AT, Khan TM et al (2012) Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers. Sci Transl Med 4:120ra17
Lovly CM, Pao W (2012) Escaping ALK inhibition: mechanisms of and strategies to overcome resistance. Sci Transl Med 4:120ps2
Sasaki T, Koivunen J, Ogino A et al (2011) A novel ALK secondary mutation and EGFR signaling cause resistance to ALK kinase inhibitors. Cancer Res 71:6051–6060
Sasaki T, Janne PA (2011) New strategies for treatment of ALK rearranged non-small cell lung cancers. Clin Cancer Res 17:7213–7218
Seto T, Kiura K, Nishio M et al (2013) 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 14:590–598
Ou S, Gadgeel S, Chiappori A et al (2013) Safety and efficacy analysis of RO5424802/CH5424802 in anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) patients who have failed crizotinib in a dose-finding phase I study (AF-002JG, NCT01588028). Eur J Cancer 49(2):LBA44
Shaw AT, Kim DW, Mehra R et al (2014) Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med 370:1189–1197
Friboulet L, Li N, Katayama R et al (2014) The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer. Cancer Discov 4:662–673
Shaw AT, Hsu PP, Awad MM et al (2013) Tyrosine kinase gene rearrangements in epithelial malignancies. Nat Rev Cancer 13:772–787
Godbert Y, Henriques de Figueiredo B, Bonichon F et al. (2014) Remarkable response to crizotinib in woman with anaplastic lymphoma kinase-rearranged anaplastic thyroid carcinoma. J Clin Oncol. 2015 Jul 10;33(20):e84–7
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2016 Springer International Publishing Switzerland
About this chapter
Cite this chapter
Ou, SH.I., Shirai, K. (2016). Anaplastic Lymphoma Kinase (ALK) Signaling in Lung Cancer. In: Ahmad, A., Gadgeel, S. (eds) Lung Cancer and Personalized Medicine. Advances in Experimental Medicine and Biology, vol 893. Springer, Cham. https://doi.org/10.1007/978-3-319-24223-1_9
Download citation
DOI: https://doi.org/10.1007/978-3-319-24223-1_9
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-24221-7
Online ISBN: 978-3-319-24223-1
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)