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 provided by Autonomous University of Puebla. Download chapter PDF
Similar content being viewed by others
Keywords
- Anaplastic lymphoma kinase rearrangement non-small cell lung cancer
- Receptor tyrosine kinase fusion positive tumors
- Crizotinib
- ALK breakapart FISH
- Chromosomal rearrangement
Molecular Basis of ALK Rearrangement in NSCLC
Chromosomal rearrangements have long been recognized as oncogenic drivers in hematological malignancies. Although it has been predicted in early 2000 that chromosomal rearrangements will be found in solid malignancies there was no reports of such rearrangements well into the mid 2000s [1]. This all changed in 2007 when two research groups independently discovered the chromosomal rearrangement in the anaplastic lymphoma kinase gene in non-small cell lung cancer [2, 3]. These two initial reports revealed in NSCLC there was both intra-chromosomal deletion and inversion of the echinoderm microtubule associated protein like 4 (EML4) gene to ALK on chromosomal 2 generating an EML4-ALK fusion protein containing the N-terminal portion of EML4 protein that retains the “coil-coiled” dimerization and the C-terminal portion of ALK which contains the kinase domain that is present in the cytoplasm and constitutively active [2]. Further elegant experiments demonstrated that transgenic mice expressing EML4-ALK in the lung results in multiple adenocarcinomas in the lung [4]. ALK is one of 58 human receptor tyrosine kinase receptors (RTKs) [5] and is the namesake rearrangement in anaplastic large cell lymphoma [6]. Although there are multiple pathways could be activated by the constitutively EML4-ALK [7], the common sequala of the ALK activation is the increase in survivin level and a decrease in pro-apoptotic BIM protein allowing lung cancer cells driven by ALK activation to escape apoptosis [8]. Since 2007, several different breakpoints in the EML4 have been identified that have been fused to the ALK generating several EML4-ALK fusion variants [9]. Currently, there are three main EML4-ALK fusion variants. The most common variant among EML4-ALK fusion is variant 1 (54.5 %) followed by variant 3 (34 %) and variant 2 (10 %) [9, 10]. Additionally, other fusion partners to ALK kinase domain have been identified in NSCLC including TFG (Trk-fused gene), KIF5B (kinesin family member 5), and KLC1 (kinesin light chain 1) [9]. As recently as in 2014 new fusion partner, HIP1 (Huntington interacting protein 1), to ALK in NSCLC is continuously being discovered [11, 12]. Indeed any protein that contains a “coil-coiled” domain that can serve as a dimerization domain and can localize to the cytoplasm can potentially act as a fusion partner to ALK. Hence it is likely more fusion partners to ALK in lung cancer will be identified in the future. Hence ALK-rearranged NSCLC is a molecularly heterogeneous subset of lung cancer. In vitro experiments have shown that there are potential differential responses among the various EML4-ALK fusion variants to various ALK inhibitors [13]. Therefore is reasonable to hypothesize that these various ALK fusion variants will have subtle but different clinicopathologic characteristics and likely differential response to ALK inhibitors. Additionally activation of epidermal growth factor receptor (EGFR) mutations have been identified in ALK-rearranged lung cancer; however, whether activation EGFR mutations and/or ALK rearrangement is the main oncogenic driver remained to be determined [9].
Clinicopathologic Presentations of ALK-Rearranged Lung Cancer
Despite being a molecularly heterogeneous disease, several general patterns can be ascribed to ALK-rearranged NSCLC. First, the median age of diagnosis of ALK-rearranged NSCLC is in the early to mid 50s which is about 15 years younger than the typical age of diagnosis of lung cancer in the US [14–16]. However the age of diagnosis can range from the early twenties to the eighties subtly underlining this is indeed a molecularly heterogeneous disease [15, 16]. Second, the vast majority (>95 %) of the ALK-rearranged lung cancer is adenocarcinoma [15, 16] with a portion of these adenocarcinoma also had signet ring features although signet ring features is not pathognomonic for ALK rearrangement [14, 17]. However, case reports have shown that ALK rearrangement has also been found in squamous cell carcinoma [11, 12, 18]. Interestingly, a recent report has shown that EML4-ALK fusion transcript is found in small cell lung cancer [19]. Thus as we broaden our screening of ALK rearrangement in all histologies of lung cancer, we may gain further knowledge about ALK rearrangement in lung cancer. Third, similar to lung cancer driven by activating EGFR mutations, between two-thirds to three quarters of ALK-rearranged lung cancer patients were never-smokers (defined as <100 cigarettes lifetime) [20]. Therefore, smoking status should not be used as a clinical criterion to determine whether to screen for ALK rearrangement in lung cancer. Fourth, unlike EGFR mutated lung cancer there does not seem to be a propensity for ALK-rearranged lung cancer to be more common in Asian patients although whether a specific variant of EML4-ALK is more prevalent among a certain racial/ethnic group remains to be determined [9]. Fifth, in terms of tumor burden and sites of metastasis at the time of initial presentation, there seems to be some differences between ALK-rearranged lung cancer and EGFR mutated lung cancer [21]. One particular interests among clinical oncologists treating ALK-rearranged lung cancer is whether there is an increase incidence of brain metastasis. This question arises from the observation that close to half of ALK-rearranged lung cancer patients who progressed on crizotinib had brain relapses. It does not seem that patients with ALK-rearranged lung cancer inherently presents with higher incidence of brain metastasis at the time of diagnosis [21].
Biology of ALK-Rearranged Lung Cancer
Our aggregate understanding of the biology of ALK-rearranged lung cancer come from differential responses ALK-rearranged lung cancers to various chemotherapy agents, the diagnostics methods used to identify ALK-rearranged lung cancer patients, patterns of relapse on crizotinib, acquired resistances during crizotinib treatment, and the clinical activity of more potent ALK inhibitors in clinical development.
A randomized trial (PROFILE1007) comparing crizotinib to single chemotherapy agent (docetaxel or pemetrexed) as second line treatment ALK-rearranged lung cancer have clearly demonstrated that crizotinib conferred statistically significant progression-free survival (PFS) [22]. However, the response rate of ALK-rearranged lung cancer patients treated with pemetrexed was much higher than those treated with docetaxel [22]. This observation is consistent with case series that reported ALK-rearranged lung cancer patients had a higher response rate to pemetrexed [23–26] likely due to a lower level of thymidylate synthase (TS) [26], which is a target of pemetrexed, in the ALK-rearranged tumor. It has been postulated that the aberrant activation of ALK lead to repressed transcription of the TS gene.
The current FDA approved companion diagnostic test which was approved simultaneously with the approval of crizotinib in August, 2011 was the Abbott Vysis breakapart fluorescence in situ hybridization (FISH) assay [9, 27]. However FISH is expensive, labor intensive, and requires certain technical competence to interpret the FISH signals [9]. Since 2011, it is becoming clear that immunohistochemistry (IHC) is a equally effective but much cheaper way to detect ALK rearrangement in lung cancer [28]. ALK IHC test using a highly sensitive antibody D5F3 can now be automated taking the observer variability out of the testing component [29]. ALK protein is not expressed in normal tissues and thus any aberrant ALK expression represents rearrangement in ALK. IHC has been used to detect ALK rearrangement in ALCL for many years using the ALK-1 antibody from Daiko. However, the promoter of EML4 is less active than the promoter for nucleophosmin that is fused to ALK in ALCL hence ALK-1 from Daiko is not a sensitive antibody for detecting ALK rearrangement in lung cancer [30]. Reverse transcription-polymerase chain reaction (RT-PCR) [10] and target deep sequencing [31] have also been used to detect ALK rearrangement in lung cancer. One of the major advantages of the sequencing approach is that the exact fusion variant is known [31] and that any unique clinicopathologic characteristics associated with each ALK fusion variant may be identified. Finally there are conflicting data on the prognostic significance of ALK rearrangement in lung cancer ranging the wide spectrum as a poor prognostic factor [32, 33] to no significance [34] to being a favorable prognostic factor [35]. In the future when next generation sequencing is in wide use then the biology of each unique ALK fusion will be even better identified and the prognostic significance of ALK rearrangement can be answered also. It is now believed that most of the ALK-rearranged lung cancer reminds dependent on ALK signaling for its pathogenesis as a majority of ALK-rearranged lung cancer patients continued to derive clinical benefit with continual ALK inhibition with an overall survival close to 30 months [36]. Hence ALK rearrangement in lung cancer is generally a favorable prognostic factor since currently there are several potent ALK inhibitors in clinical development and the motto of precision cancer medicine of “the right drug for the right disease” did certainly prolong life [34].
Treatment of ALK-Rearranged Lung Cancer
The discovery of ALK rearrangement in lung cancer would have been a historical academic footnote for awhile had it not been the existence of a phase I trial of crizotinib, a multi-targeted MET/ALK/ROS1 inhibitor [15, 16]. Crizotinib was initially being developed as a MET inhibitor [37] but its anti-ALK activity was known [38]. The discovery of a RTK rearrangement in a common epithelial malignancy is unexpected but the crizotinib phase I investigators and Pfizer were able to modify the protocol to accommodate this newly discovery cohort of molecularly defined patients. Within 2 years crizotinib was able to show impressive anti-tumor activity with overall response rate of approximately 60 % and progression-free survival of approximately 9 months essentially independent of the line of therapy [15, 16]. Based on the expanded phase I and a global phase 2 study of crizotinib received US FDA approval on August 26, 2011 for the treatment of advanced ALK-rearranged lung cancer [9]. Subsequently crizotinib has been demonstrated to be superior to chemotherapy in first-line (Pfizer Press release, March 25, 2014) or second-line treatment of ALK-rearranged lung cancer [22] in terms of statistically significant improved progress-free survival.
Invariably, these patients develop disease progression while on crizotinib. Many of these patients are likely to be still dependent on ALK signaling as they can benefit from continuation of crizotinib beyond treatment especially if the new and/or progressing metastatic site can be controlled by loco-ablative therapy [36, 39]. Recent retrospective analysis of data of crizotinib trials suggested progression free survival from the date of progression among patients who continued crizotinib beyond progressive disease (CBPD) was 16.4 months comparing to 3.9 months who discontinued crizotinib at progression (Hazard ratio [HR] 0.27, 95 % confidence interval [CI]: 0.17−0.42; p < 0.0001) [36] and an overall survival of 29.6 months among CBPD patients comparing to an overall survival of 10.8 months among patients who discontinued crizotinib on progression (HR 0.30, 95 % CI: 0.19−0.46; p < 0.0001) [36]. Furthermore the continual dependence of ALK signaling was the phenomenon of “disease flare” where there is rapid tumor progression when crizotinib is discontinued after the patient has progressed on crizotinib [40]. We can generally view there are two major mechanisms that result in disease progression on crizotinib. First close to 50 % of patients on crizotinib will develop progression in the brain (new or existing) likely indicating a pharmacodynamics failure of crizotinib to reach adequate therapeutic level in the central nervous system (CNS) [41]. Second the ALK gene acquired secondary resistance mutations to crizotinib including gatekeeper mutation (L1196M) and solvent front mutations (G1202R) [31, 42–46]. There are other resistance mechanisms reported such as activating of other by-pass signaling pathway such as EGFR [46] or the loss of ALK dependence altogether [43]. There are now several more potent ALK inhibitors in clinical development (ceritinib, alectinib, AP26113, ASP3026, X396, TSR-011, PF0663922, RXDX101) [47]. Among these ALK inhibitors, alectinib [48, 49] and ceritinib [50] are the farthest along in clinic development where phase I results of both compounds have been published or presented and global phase 2 trial of both compounds in crizotinib-resistant patients have been completed. In general most of the ALK inhibitors can overcome most of the acquired resistance mutations except the solvent-front mutation G1202R [31, 51]. Thus an ideal ALK inhibitor for the treatment of ALK-rearranged lung cancer should have two major properties: the ability to penetrate CNS and have clinical activity in existing brain metastasis and the ability to overcome secondary acquired ALK mutations especially the solvent front mutation G1202R. However there are evidence both in vitro and from patient series that these ALK inhibitors have differential sensitivity to the various secondarily acquired mutation [13, 31, 52]. Thus rebiopysing crizotinib resistant tumor to try to understand exactly the resistance mechanism(s) will be necessary to tailor the treatment and serve as a paradigm for precision cancer medicine. Crizotinib and other ALK inhibitors in clinical development have put ALK-rearranged lung cancer in the parlance of precision oncology medicine. We also gained insight into the biology of ALK-rearranged lung cancer when we understand the mechanism of resistance to these inhibitors.
Future Perspective
One of the most commonly asked questions is what cause(s) ALK rearrangement in lung cancer. While no one has generated specific scientific data that can answer this one particular question, one can speculate knowing that there are RTK rearrangements are found in other common solid epithelial malignancies and the same fusion partners are found in different RTK [52], there may be chromosomal breakpoints in the cancer genome that is susceptible for intra- and interchromosomal rearrangement during DNA replication. Nevertheless the exact triggering event still eludes us. ALK rearrangement has been found in colon, breast, [52] and even thyroid cancer where one thyroid cancer patient with EML4-ALK rearrangement has responded to crizotinib [53]. Thus ALK signaling in lung cancer serves as a paradigm for future understanding of ALK signaling in other common epithelial malignancies and in broader perspective RTK rearrangement in epithelial malignancies [52].
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)