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Inhibition of ALK Signaling for Cancer Therapy
Yael P. Mossé, Andrew Wood and John M. Maris Clin Cancer Res 2009;15:5609-5614. Published OnlineFirst September 8, 2009.
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University of Pennsylvania School of Medicine. 5. Mossé. and neuroblastoma. 1). DOI:10.P.edu. accepted 5/28/09. This review focuses on the normal and cancer-related biology of ALK and the preclinical proof-of-principle for ALK as a therapeutic target. and cell shaping. Philadelphia. 2009. Wood).aacrjournals. cell migration. and exploiting this transdisciplinary knowledge therapeutically.620Authors' Affiliations: 1Division of Oncology and Center for Childhood Cancer Research. 2Department of Pediatrics. and 3Abramson Family Cancer Research Institute. Recently it has become clear that ALK is one of the few oncogenes activated in both hematopoietic and nonhematopoietic malignancies. The absence of published structural studies of ALK extracellular and intracellular domains.Published OnlineFirst September 8.1158/1078-0432. Fax: 215-590-3770. Recent progress in the elucidation of the major canonical signaling pathways postulated to be activated by NPM-ALK signaling has provided insight into which pathways may present a rational therapeutic approach. Maris.M. and that these mutations can also be somatically acquired (7–10).15(18) September 15. the Fulbright Foundation (A. and the conflicting literature over whether pleiotrophin (13. PA 19104-4318. Maris). ref. Children's Hospital of Philadelphia.15(18):5609–14) Background Anaplastic lymphoma kinase (ALK) is an orphan receptor tyrosine kinase first identified as part of the t(2. Philadelphia. and signaling. Although constitutive ALK signaling has been shown in these contexts to induce cell transformation in vitro and in vivo by controlling key cellular processes such as cellcycle progression. The ALK gene encodes a 1.2 and John M. inflammatory myofibroblastic tumors. University of Pennsylvania School of Medicine. understanding their detailed molecular mechanisms. and overexpression (Fig. A variety of human malignancies have anaplastic lymphoma kinase (ALK) translocations.M.org Downloaded from clincancerres. Regardless. it is now clear that ALK represents a tractable target for innovative therapies on the basis of selective inhibition of its tyrosine kinase activity. Requests for reprints: John M. Role of ALK in Cancer A variety of mechanisms that lead to aberrant ALK signaling in a variety of human cancers have been characterized. mutations. The extracellular region of ALK shows significant homology to the leukocyte tyrosine kinase (11). doi:10. non–small cell lung cancer. revised 5/22/09. which places ALK in the insulin receptor superfamily of RTKs. Phone: 215-590-5242. or oncogenic mutations. resulting in the generation of oncogenic ALK fusion genes and their encoded proteins.M. The identification of the downstream effector pathways controlled by ALK should pave the way for the rational design of ALK-inhibition therapies for the treatment of a subset of human cancers that harbor ALK aberrations. including anaplastic large cell lymphoma. Maris). Importantly. amplifications. It has also recently been discovered that germline mutations in ALK are the major cause of hereditary neuroblastoma (7).1158/1078-0432. and non-small cell lung cancers (NSCLC. 14) and/or midkine (15) are ALK ligands.aacrjournals. 3).1. These oncogenic fusion proteins lead to constitutive activation of the ALK kinase domain and have been identified in various solid tumors. the canonical signaling pathways and cell-type specificities of signaling remain poorly defined. with acquired somatic mutations seen in the more common sporadic form of the disease. Maris). Grant support: National Institutes of Health (NIH) grants K08-111733 (Y. squamous cell carcinomas (4). function. R01-CA124709 (J. Pennsylvania Received 5/14/09.CCR-08-2762 amino acid protein that undergoes posttranslational N-linked glycosylation to a fully mature form weighing 220 kDa. and these include translocations or structural rearrangements.1. 2009 . F 2009 American Association for Cancer Research. Maris1. and the Giulio D'Angio Endowed Chair (J. R01-CA78454 (J. Mossé). including inflammatory myofibroblastic tumors (IMT. missense germ-line mutations in the tyrosine kinase domain have been described in patients with hereditary neuroblastoma. 2013 Copyright © 2009 American Association for Cancer Research 5609 Clin Cancer Res 2009. ref.2. It has recently become clear that many human cancers activate ALK signaling by creating unique oncogenic fusions of the ALK gene at chromosomal band 2p23 with a variety of partners through chromosomal translocation events (2). Recent data suggest that deregulation www. ALK gene amplification. (Clin Cancer Res 2009. survival.CCR-08-2762 Molecular Pathways Inhibition of ALK Signaling for Cancer Therapy Yael P. Children's Hospital. 6).org on February 27. ALK Fusion Proteins-Translocations Translocations are the most common known cause of genomic ALK aberration.2 Andrew Wood.5) chromosomal translocation associated with most anaplastic large cell lymphomas (ALCL) and a subset of T-cell non-Hodgkins lymphomas (1).3 Abstract Paradigm shifting advances in cancer can occur after discovering the key oncogenic drivers of the malignant process. published OnlineFirst 9/8/09. E-mail: maris @chop. This finding has focused intense interest in inhibiting ALK signaling as an effective molecular therapy against diseases with ALK-driven pathways. ALK expression is restricted to the developing central and peripheral nervous system with a postulated role in participating in the regulation of neuronal differentiation (12). emphasizes that much remains to be learned about ALK structure.
of several genes (Fra 2 on 2p23. In physiological ALK signaling. ligand-induced homo-dimerization of the extracellular domains is hypothesized to bring the tyrosine kinase domains into sufficient proximity to enact trans-phosphorylation and kinase activity.15(18) September 15. and nucleolus (2). A. through phosphorylation of tyrosine and serine residues. D. The remaining 20% of translocations fuse ALK to other partners that commonly encode coiled-coil oligomerization domains such as Tyrosine Receptor Kinase-fused gene (TFG).aacrjournals. but no overlap with NSCLC. Within the truncated nucleophosmin protein the essential domain required for transformation is a coiled-coil oligomerization domain. The truncated NPM also encodes a nucleolar localization domain that explains why in contrast to other ALK fusions. 2009.Published OnlineFirst September 8. or amplification of wild-type ALK mediating overexpression. C. ligand-induced dimerization of the extracellular domain of ALK monomers leads to trans-phosphorylation of the tyrosine kinase (TK) domain and physiological ALK signaling. By contrast. nucleus.aacrjournals. In ALCL. Site-directed mutagenesis of the dimerization domain abrogates NPM-ALK-transforming activity suggesting that proximity of the ALK kinase domains is a prerequisite to facilitate trans-phosphorylation of the partner kinase (19).org . NPM-ALK can be detected in the cytoplasm. Signal Transducers and Activation of Transcription protein 3 may couple cell growth to increased oxidative phosphorylation. and about the same frequency of ALCLs stain positive for ALK by immunohistochemistry (17. whereas most fusion products are largely cytoplasmic.q35) translocation. and transactivation of the TK domain. ALK signaling cooperates with other genetic aberrations.1158/1078-0432. fusion partners facilitate approximation of truncated ALK containing the TK domain through coiled-coil domains or subcellular localization. E. translocations have not been detected in neuroblastoma specimens. 18). 1. Approximately 70 to 80% of ALK-positive ALCL express the nucleophosmin-ALK (NPM-ALK) fusion protein derived from the t(2.org on February 27. B.CCR-08-2762 Molecular Pathways Fig. spontaneous dimerization. ligand-independent signaling is induced by activating mutations within the TK domain. Clin Cancer Res 2009. and that aberrant transcriptional activity of certain genomic regions is linked to their propensity to undergo chromosomal translocations (16). Mutations and amplification are unique to neuroblastoma but rarely co-occur. Cancers dysregulate ALK via multiple mechanisms. leading to unregulated constitutive kinase activity and malignant transformation. translocations resulting in pathogenic fusion partners provide dimerization domains that are ligand independent. respectively. and the CSF1 receptor on 5q33. 2013 Copyright © 2009 American Association for Cancer Research 5610 www. ALCL and IMTs have unique and shared fusion partners. DOI:10. AKT stabilizes the GLI1 protein that is upregulated via amplification of the Sonic Hedgehog locus. 2009 Downloaded from clincancerres.5)(p23. HLH protein Id2 on 2p25.1) located near the ALCL translocation breakpoint occurs before the formation of translocation events. representation of ALK aberrations in human cancers and major signaling pathways activated through NPM-ALK. constitutive ALK signaling induces transformation via canonical signaling networks.
Transient siRNA knockdown directed against ALK in neuroblastoma cell lines showed significant inhibition of growth restricted to cells with evidence for ALK activation. in a mutation-specific manner. As we define the frequency of occult germline mutations and further understand the role of ALK in the initiation of neuroblastomas without a family history. most common in Asian nonsmokers or light-smokers with the adenocarcinoma subtype of NSCLC. 25. ALK activation by mutation and/or amplification is functionally relevant in models of high-risk neuroblastoma. similar to what is seen at the MET locus in hereditary renal papillary cancer (38). Interest in pharmacological inhibition of ALK has most recently been spurred by the discovery of transforming echinoderm microtubule associated protein like 4-anaplastic lymphoma kinase (EML4-ALK) fusions in a subset of NSCLCs (5). Although these data are still emerging. but not yet proven. Because there are noninvasive methods to screen for neuroblastoma (urinary catecholamine metabolites have relatively high sensitivity and specificity for detecting disease). We and others have shown that ALK is expressed in the majority of human neuroblastoma-derived cell lines. pharmacologic inhibition with a highly specific small molecule inhibitor of ALK currently in phase 1 clinical trials (PF-02341066. or NKX2-1 aberrations (23–26). and CLTC (32). including TPM3 and TPM4 (30). 2013 Copyright © 2009 American Association for Cancer Research 5611 Clin Cancer Res 2009.7% in Japanese NSCLC tumor samples (5). and is only minimally responsive to conventional chemotherapy or radiation therapy. Baf3 cells expressing the two most common mutations showed cytotoxicity to NVP-TAE684. and it seems that disease penetrance may be attributable to mutation type as rarer mutations. The deregulated expression of full length ALK and ALK fusions has recently been observed in several nonlymphoid neoplasms. Immunohistochemical ALK reactivity occurs in 56% of cases and is restricted to the cytoplasm consistent with the observation that NPM-ALK translocations do not occur in this disease. but there seem to be mutation-specific differences in sensitivity. it is somewhat clear that ALK phosphorylation status is a good biomarker for sensitivity to pharmacologic inhibition. NVP-TAE684 has been shown to block the growth of ALCL-derived and ALK-dependent cell lines with IC50 values between 2 and 10 nM. but not to date with fusion partners seen in NSCLC. but subsequent studies showed lower frequencies of 3% or less (24. Epidemiologic characterization of EML4-ALK translocations is ongoing but it seems to be a rare aberration. a small molecular competitive inhibitor of ATP binding in the ALK kinase domain (40). forming a distinct subgroup from patients harboring EGFR. Dimerization is enabled as the truncated EML4 protein retains a coiled-coil oligomerization domain in a manner similar to NPM-ALK.org on February 27. IMT is associated with various ALK translocations that overlap with those found in ALCL. CARS (31). was associated with very low penetrance compared with the near complete penetrance seen with the R1275Q mutation. it is now only used as a tool compound (40). however. NPM-ALK transgenic mouse models have shown T-cell transformation as well as B-cell lymphomas (21) and may be useful in the evaluation of new therapeutic agents for these diseases. we currently recommend genetic testing of the proband in any case in which there is a first or second degree relative with neuroblastoma. Although the number of families studied remains relatively small. heritable mutations have been restricted to the kinase domain of ALK. There are also several nonnuclear ALK fusion chimeras that induce transformation in vitro. they show slight differences in pathway activation. The clathrin heavy chain-like gene (CLTCL). such as G1128A seen in one large pedigree. and it is presumed. Mutations and Genomic Amplification Expression of ALK has been reported in a large fraction of human-derived neuroblastoma cell lines (34). 27). both germline (7) and somatic (7–10) mutations that activate ALK have been discovered in neuroblastoma. an often lethal embryonal malignancy that contributes 15% to the overall childhood cancer mortality rate (37).org Downloaded from clincancerres. there is often parental interest in testing even when there is no objective evidence for hereditary predisposition. that the second hit is somatic gain or amplification of the mutant allele. and a recent report of a novel fusion transcript. Heritable gain-of-function mutations in ALK are the cause of most hereditary neuroblastoma cases.1158/1078-0432. KRAS. This fact compounds the already controversial topic of the role for genetic screening in this disease. and Tropomyosin 4 (TPM4). IMT is a rare tumor of mesenchymal origin that arises in multiple tissues. kinesin family member 5B-anaplastic lymphoma kinase (KIF5B-ALK). Although almost all ALK fusions retain the same portion of ALK because of translocation events that result in loss of the entire extracellular portion of normal ALK as well as the transmembrane segment. 2009. see Clinical Translational Advances) showed potent antitumor activity in preclinical models of neuroblastoma both in vitro and in vivo. it is apparent that the R1275Q mutation is most common.Published OnlineFirst September 8. due to its toxicity profile. and our group and others had previously identified ALK as a candidate neuroblastoma oncogene through somatically acquired amplification of the genomic locus (35. suggesting that ALK activation can occur by mechanisms other than mutation within the kinase domain. possesses metastatic potential (29). Both mutations fall within the kinase activation loop in a region strongly associated with activating mutations seen in other oncogenic kinases (7). Because neuroblastoma often occurs in families with other young children or plans for future children. The initial frequency of EML4-ALK fusion transcripts was approximately 6.aacrjournals. 36). but frequency and significance of this has not been fully defined (33). and cocrystallization with www. or the proband has multifocal disease consistent with hereditary predisposition. for example. and that ALK expression is significantly higher in neuroblastoma cells harboring ALK mutations (39). likely because of differences in their subcellular compartmentalization and/or cell-type. To date. Analysis of protein lysates from these lines showed constitutive phosphorylation in each of the cell lines harboring mutations.CCR-08-2762 ALK Inhibition Therapy Tropomyosin 3 (TPM3). encodes a clathrin family member that coalesces to produce cytoplasmic vesicles of CTLC-ALK bringing the ALK tyrosine kinase domains into close proximity (20).15(18) September 15. one of the few pediatric tumors to be initiated by gain-of-function mutations. DOI:10. Direct demonstration of EML4-ALK as a dominant oncogenic driver in NSCLC includes transformation of mouse 3T3 fibroblastic cells with forced overexpression of human EML4-ALK and de novo lung adenocarcinoma formation in mice engineered to express EML4-ALK targeted to the lung alveolar epithelial compartment (28). in this disease (22). with weak phosphostaining in a smaller subset of wild-type cell lines.aacrjournals. Solving the crystal structure of the ALK kinase domain. More recently. Recently. A subset of esophageal cancers show the TPM4-ALK fusion protein. and thus might offer a tractable therapeutic target. screening recommendations can be solidified. 2009 .
SHH/GLI1 activation is the result of SHH gene amplification and is further mediated by NPM-ALK through activation of PI3K/AKT and stabilization of GLI1 protein (51). Inhibition of downstream signal transduction proteins. 1. DOI:10. as the first ALK inhibitor to enter phase 1 clinical trials. These pathways are typically upregulated in transformed cell lines (48). 50). and this may be critically important to properly evaluate future ALK inhibitor clinical trials. In contrast. This offers potentially novel therapeutic options for an otherwise lethal brain tumor. Recent work has shown that the sonic hedgehog signaling pathway (SHH/GLI1) is also activated in ALK-positive ALCLs (51). 45). however. survival. and recent work suggests that ALK immunohistochemistry may have utility as a screening tool or surrogate marker for EML4-ALK fusion gene-positive NSCLC tumors (43).Published OnlineFirst September 8. and cell cycling. ATIC phosphorylation enhances enzymatic activity of NPM-ALK (52). ALK has previously been shown to be upregulated and functionally relevant in glioblastoma. such as STAT3. This orally bioavailable small molecule inhibitor caused complete regression of NPM-ALK xenografts at pharmacologically relevant doses. and recent work has shown that ribozyme-mediated knockdown of ALK results in abolishment of tumor growth in a xenograft model (42). 2). Expression ALK expression is of uncertain pathogenic significance in several human cancers. even though STAT3 anti-sense oligonucleotides suppress the in vivo transforming activity of NPM-ALK (45). 2009 Downloaded from clincancerres. 55). altered kinase substrate specificity. PF-02341066. Among the potential combinations of proteins phosphorylated by ALK kinase activity. and are key effectors of cell proliferation and differentiation.CCR-08-2762 Molecular Pathways pharmacologic inhibitors. Inhibition of this pathway induces apoptosis and cell cycle arrest. but display no overlap with NSCLC. Kinases are critical components of cellular signal transduction cascades. especially for the development of rational combination therapies. which control cell proliferation. with a strong correlation between antitumor response and abrogation of phosphorylation of ALK (50). defining the downstream signaling pathways that mediate the effects of ALK activity in the context of a neuroblastic cell will also be critical. Clinical Translational Advances Small molecule tyrosine kinase inhibitors. as well as the detection of higher ALK expression in tumor compared with neighboring normal tissue (15). Different ALK fusion proteins transfected into NIH3T3 cells produced clones with differential signaling and phenotypic differences beyond those that could be explained by the variable kinase activity of each fusion. was initially designed to inhibit c-Met. TPM interacts with endogenous tropomyosin in the cytoskeleton. AKT/PI3K (46).aacrjournals. and EGFR impair drug binding as the major mechanism of acquired resistance to kinase inhibitors. It has been postulated that the STAT family is unlikely to play a key role of the pathogenesis of EML4-ALK (53). TPM3-ALK invasive capacity may partly be mediated by a unique pathogenic mechanism.aacrjournals. has been shown to prevent NPM-ALK induced transformation in vivo (45). Work is ongoing to characterize the full spectrum of germline and somatic DNA alterations leading to ALK activation to develop strategies for future clinical trials on the basis of inhibiting ALK-mediated signaling in neuroblastoma. The constitutive activation of ALK fusion proteins leads to cellular transformation through a complex signaling network. but was also found to have significant activity against ALK (50). recognition of the variety of malignancies in which ALK plays a causative role has prompted broad developmental efforts in this area. 2013 Copyright © 2009 American Association for Cancer Research 5612 www. altered sequences of tyrosine auto-phosphorylation. KIT. PF-02341066 is currently the only available ALK small-molecule inhibitor in clinical trials. Point mutations in the kinase domain of other tyrosine kinases such as BCR-ABL.1158/1078-0432. Immunohistochemical detection of ALK protein overexpression is pathognomonic for ALCL. and to understand how resistance mutations may arise under selective pressure. it has been postulated that the most important effects involve activation of STAT3 (44. TPM3-ALK cells showed the most AKT phosphorylation and migratory capacity in vitro. Differential Activation of Downstream Signaling Pathways The critical pathways involved in transformation because of dysregulated ALK signaling are best characterized by translocations that juxtapose ALK to dimerization partners (Fig. suggesting that inhibition of SHH/ GLI1 signaling in combination with blocking NPM-ALK and/or the PI3K/AKT pathway may present a rational therapeutic approach in ALK+ ALCL. In addition. and these lessons are readily applicable to ALK kinase inhibition. ref. Different ALK aberrations produce diverse pathogenic signaling anomalies through a combination of differentially activating common signal transduction pathways and unique pathogenic mechanisms. and ATIC-ALK cells cause STAT3 phosphorylation with only modest invasion and in vivo tumorigenicity (48). Tissue context and signaling differences may explain why some ALCL and IMT share some fusion partners. This is significant. 2009. The detection of ALK mRNA in diverse human tumor-derived cell lines (41). tissue context. These signaling variations could arise because of multiple mechanisms including: variable subcellular localizations of activated ALK.org . investigators have generated several ALK mutants in the kinase domain and evaluated their kinase activity and sensitivity to inhibition by two ALK inhibitors Clin Cancer Res 2009. and by breakpoints disrupting the original loci in which truncated genes are translocated from. There now exists clear precedent in clinical oncology that robust antitumor activity can be obtained with inhibitors directed toward oncogenic tyrosine kinases that are genetically dysregulated (54. but in vivo tumorigenicity was less than that observed in NPM-ALK cells. likely reflects physiological expression rather than seminal pathogenic events (41). To begin to address this. and RAS/ERK (47) pathways.org on February 27. autocrine or paracrine ligand effects. which is hypothesized to alter cytoskeletal organization and led to greater motility and metastatic potential (29). Additional signaling and phenotypic variation will likely be discovered when the full spectrum of mutated ALK and pathogenically overexpressed wild-type (via genomic amplification) proteins are studied. Imatinib showed that off-target kinase inhibition could be rationally exploited because of its efficacy in Kit+ gastrointestinal stromal tumors (56).15(18) September 15. will be necessary to understand if some mutations confer resistance. Currently work is focused on developing reliable techniques for phospho-ALK staining in routine clinical specimens. and pharmacological inhibition of ALK leading to apoptosis abrogates phosphorylation of these key signal-transducing proteins in ALCL models (49.
et al. et al. Clin Cancer Res 2009. Oncogene 1997. A pediatric trial of PF-02341066 will begin enrollment of subjects in 2009. EML4ALK fusion transcripts. Identification of squamous cell carcinoma associated proteins by proteomics and loss of beta tropomyosin expression in esophageal cancer. EML4ALK lung cancers are characterized by rare other mutations. a TTF-1 cell lineage. 10. Morris SW.96:3681–95. Defining the epidemiology of ALK aberrations in each cancer that harbors ALK pathway activation seems essential to properly design and interpret clinical trials of ALK inhibitors. NPMALK transgenic mice spontaneously develop T-cell lymphomas and plasma cell tumors. 21. 11. Takeuchi K. et al. Lastly. Mathas S. Nature 2008. Longo L. there are compelling data to support the hypothesis that tumors with ALK aberrations exhibit oncogene addiction. et al. Choi YL. Binding of these inhibitors to wild-type and mutant ALK was analyzed using homology models. Rikova K. 14. Foss HD. Vigny M. So KK. but no NPM-. et al. Sanda T. et al. Wagner PL.Published OnlineFirst September 8. 8. There is strong rationale and significant enthusiasm toward ALK inhibition as a targeted therapy against tumors harboring oncogenic fusions or activating mutations. It remains to be seen whether newer inhibitors designed with greater specificity against ALK will eventually prove superior to multikinase inhibitor. Hawkins AL. Future Developments ALK is one of the few examples of a receptor tyrosine kinase implicated in the oncogenesis of both hematopoietic and nonhematopoietic malignancies. Aigner A. CLTC-. Takada S. 25.115: 1723–33. et al. Meaburn KJ. ALK. World J Gastroenterol 2006. 2. Togashi Y. The anaplastic lymphoma kinase in the pathogenesis of cancer. Although the importance of autocrine-paracrine growth loops involving normal ALK in tumorigenesis is not yet fully elucidated. Kirstein MN.106:5831–6. 15. CD30(+) anaplastic large cell lymphoma: a review of its histopathologic.455:967–70. et al. Wong DW. Morris SW. Takeuchi K. and plans are currently being made for how to properly integrate ALK inhibition therapy into frontline chemotherapeutic regimens. et al. Fujimoto J. 24. Janoueix-Lerosey I. it is clear that for cancers that can usurp ALK signaling as a mechanism of oncogenicity. Henkle C. Nature 2007. et al.5:154–8. in non-small cell lung carcinomas. Dvorak C. 7. Besides the use of selective ALK inhibitors. et al. et al. 22. a receptor tyrosine kinase expressed specifically in the nervous system. ALK pathway status must be assayed for at the time of diagnosis or relapse. 127:707–22. Diagn Mol Pathol 1996. Enomoto M. Midkine binds to anaplastic lymphoma kinase (ALK) and acts as a growth factor for different cell types. Ambrogio C. Ellingham T. Nature 2008. Koivunen JP. Demichelis F. Science 1994. Additional studies are required to determine whether tumors that express full-length ALK that is activated by its ligand exhibit the same or at least partial dependence upon ALK growth signals. Malekzadeh R. Furthermore. Zeng Q. Activating mutations in ALK provide a therapeutic target in neuroblastoma.59:2776–80. et al. Kuo A. Chiarle R. Naeve C. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Disclosure of Potential Conflicts of Interest No potential conflicts of interest were disclosed. Perlman EJ.263:1281–4. Cautious extrapolation from preclinical models and inhibitorkinase co-crystallization studies will help us to define biomarkers predictive of therapeutic response. Durkop Hu. 12. Identification of ALK as a major familial neuroblastoma predisposition gene. TPM3-. Choi YL.61:163–9. leading to ongoing efforts to select patients for these trials based on ALK translocation status. Mathew P. Mermel C. Oncogene 1997. genetic. Gong JZ. Leung EL. it may be crucial to develop strategies to inhibit multiple targets involved in the ALK-signaling pathway. 19. In contrast to agonist monoclonal antibodies. Guasparri I. Soda M. Elenitoba-Johnson KS. encodes a novel neural receptor tyrosine kinase that is highly related to leukocyte tyrosine kinase (LTK). et al. Stoica GE. and showed that some of the mutants are resistant to select small molecule inhibitors. to a nucleolar protein gene. Piva R. et al.org on February 27. Further demonstration of the diversity of chromosomal changes involving 2p23 in ALK-positive lymphoma: 2 cases expressing ALK kinase fused to CLTCL (clathrin chain polypeptide-like). Wen D. Shinmura K. Takeuchi K. J Biol Chem 2002.455:930–5. in non-Hodgkin's lymphoma. Greenland C. Jazii FR. 4.15(18) September 15. Fusion of a kinase gene. and young onset. EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Nat Rev Cancer 2008.12:7104–12.277:35990–8. 2009. et al. Takita J. Stein H.131:1190–203. A mouse www. 26. Mod Pathol 2009. ALK. Cell 2007. 2009 . Najafi Z. siRNA screens of the druggable genome in combination with ALK inhibitors.org Downloaded from clincancerres. Neoplasia 2008. DOI:10.14:439–49. Lamant L. Lung Cancer 2008. Zejnullahu K. Anaplastic large cell lymphoma. Lequin D. J Biol Chem 2001. Am J Clin Pathol 2007.1158/1078-0432. Touriol C. 2013 Copyright © 2009 American Association for Cancer Research 5613 Clin Cancer Res 2009. Powers C. EML4-ALK fusion lung cancer: a rare acquired event. Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma. the development of monoclonal antibodies against ALK should be pursued. and the results of the first clinical trial testing the PF-02341066 dual c-Met/ALK inhibitor has shown clinical activity in highly refractory patients with tumors harboring ALK translocations.5) in non-Hodgkin's lymphoma. Iwahara T. Clin Cancer Res 2008. Blood 2003. Chen Y.aacrjournals. and an approach that may prove to be particularly useful for tumors with ALK gene amplification. Nature 2008. a Novel Fusion Oncokinase Identified by an Immunohistochemistry-based Diagnostic System for ALK-positive Lung Cancer. References 1. Brugieres L. both C-terminal truncated form and full length form of Pleiotrophin failed to activate vertebrate ALK (anaplastic lymphoma kinase)? Cell Signal 2007.19:2434–43. et al. Kuo A. Medeiros LJ. 13. Valentine MB. Blood 2000. a precedent set by the development of monoclonal antibodies against members of the EGFR family. the chromosome 2 gene locus altered by the t(2. Gene deregulation and spatial genome reorganization near breakpoints prior to formation of translocations in anaplastic large cell lymphoma. Kageyama S. Cavalchire G. 18. Soda M. 276:16772–9. co-development of small molecular and monoclonal antibody inhibitors of ALK activation seems prudent.455:975–8. et al. Hanna M.455:971–4.CCR-08-2762 ALK Inhibition Therapy developed from different chemical series (57). Cancer Res 1999. as potency will likely be variable on the basis of the mechanism for pathway activation. and preclinical testing for synergy and antagonism with existing chemotherapy backbones will be important to maximize efficacy. Stoica GE. If the preclinical models do indeed predict what will be observed in the clinic. Mazot P.95: 3204–7. with inhibition of aberrant ALK signaling resulting in marked antitumor efficacy in preclinical models. 23. Inamura K. Choi YL. et al. 9. Molecular characterization of ALK. George RE. Oncogenic mutations of ALK kinase in neuroblastoma. 17. Kreher S.8: 11–23.10:298–302. an acinar histology. The EML4ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS. Blood 2000. 6. et al. Perner S. 16. Detection of the NPM-ALK genomic rearrangement of Ki-1 lymphoma and isolation of the involved NPM and ALK introns. Mathivet T.448: 561–6. 3.22: 508–15.14:4275–83. Nature 2008. or TFG-ALK fusion transcripts. Identification of anaplastic lymphoma kinase as a receptor for the growth factor pleiotrophin. Tao H. et al. and clinical features. KIF5BALK. et al. Guo A. Inghirami G. Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Voena C. ATIC-. et al. Proc Natl Acad Sci U S A 2009. 5.14:2175–88.101:1919–27. Laudenslager M. Cancer 2009.aacrjournals. Mosse YP.15:3143–9. Togashi Y. and the emergence of resistance mechanisms almost assured. NPM. Recurrent involvement of 2p23 in inflammatory myofibroblastic tumors. Chiarle R. Griffin CA. 27. Ladanyi M. 28. 20.
55.15(18) September 15. Bridge JA. Am J Pathol 2000. et al. Lamszus K. Rappaport E. Osajima-Hakomori Y. Wlodarska I. 50. 2009.113:2776–90. 45. Christensen JG. et al. Proc Natl Acad Sci U S A 1997. et al. Heinrich MC. Wasik MA. and efficacious inhibitor of NPM-ALK. Vasmatzis G.100:49–56.156:1711–21. Kim S. Bischof D.Published OnlineFirst September 8. Fahnrich S.2:e255. Ghose AK. et al. et al. PF-2341066.21:4342–9. 49. Steinberg F.48:3600–9. a novel inhibitor of anaplastic lymphoma kinase and c-Met. Eur J Cancer 2007. Li S. Lamant L. Neuroblastoma. 2013 Copyright © 2009 American Association for Cancer Research 5614 www. Proc Natl Acad Sci U S A 2006. Lee JH. 47. Lis Y. et al. Corless CL.org . 36. 40. selective. Enhanced antitumorigenic effects in glioblastoma on double targeting of pleiotrophin and its receptor ALK. Duplantier MM. McDermott U. 41. Proc Natl Acad Sci U S A 2007. Stat3 is required for ALK-mediated lymphomagenesis and provides a possible therapeutic target. Hieblot C.167:213–22. Anaplastic lymphoma kinase immunoreactivity correlates with ALK gene rearrangement and transcriptional up-regulation in non-small cell lung carcinomas. 43. Iafrate AJ. Zou HY. Peschel C. Gray NS. Lancet 2007. Am J Pathol 2001. 23:6071–82. Differential effects of X-ALK fusion proteins on proliferation. Blood 2009. Quail MR. Nature 2001. 44. Sakai R. Kanamori M. 29. Proc Natl Acad Sci U S A 2008. Cell 2000. Int J Cancer 2002.68: 3389–95. Oncogene 2004. Zhang Q. Mano H. Genomic alterations of anaplastic lymphoma kinase may sensitize tumors to anaplastic lymphoma kinase inhibitors. Grzelinski M.org on February 27. Duyster J. Activating mutations for the met tyrosine kinase receptor in human cancer. Li Q. Melnick JS. Voena C. An orally available small-molecule inhibitor of c-Met. 48. Expression and functional analysis of the anaplastic lymphoma kinase (ALK) gene in tumor cell lines. Delsol G. Attiyeh E. Zou HY. Biological role of anaplastic lymphoma kinase in neuroblastoma. et al. et al. Jeffers M. PLoS One 2007. 38.6: 3314–22. et al. et al. in anaplastic large-cell lymphoma and inflammatory myofibroblastic tumor. Becker E. Cools J. Blume-Jensen P. Expression of the ALK tyrosine kinase gene in neuroblastoma. Maris JM. Martens T. Proteomic profiling of proteins dysregulted in Chinese esophageal squamous cell carcinoma. Sonic hedgehog signaling pathway is activated in ALK-positive anaplastic large cell lymphoma. Hunter T. 57. Cancer Res 2007.34: 354–62. Cancer Sci 2008. Chiarle R. Lamant L. Lin DC.369:2106–20. Cai H. 31. 54. Integrative genomics identifies distinct molecular classes of neuroblastoma and shows that multiple genes are targeted by regional alterations in DNA copy number.11:623–9. Simmons WJ. Drexler HG. DOI:10. in experimental models of anaplastic large-cell lymphoma. et al. Armstrong F. 2009 Downloaded from clincancerres. Wang Q. 32. Cancer Res 2006. 33. et al. et al. 39. 34. TPM3-ALK expression induces changes in cytoskeleton organisation and confers higher metastatic capacities than other ALK fusion proteins. 51.aacrjournals. exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms. transformation. Clin Cancer Res 2009. 30. Somers R. J Mol Med 2007. Dirks WG. Du XL. Lu L. Hum Pathol 2009.157:377–84. Nakagawa A. Mol Cancer Ther 2007. Demetri GD.66: 6050–62. Liu X.1158/1078-0432.103:211–25. Nucleophosmin/anaplastic lymphoma kinase (NPM/ALK) oncoprotein induces the T regulatory cell phenotype by activating STAT3. 53. Cytoreductive antitumor activity of PF-2341066. Blood 2000. Trempat P. Armstrong F. George R. Miyake I. 52.94:11445–50.99:2349–55. Nat Med 2005. Schlessinger J. The enzymatic activity of 5-aminoimidazole-4carboxamide ribonucleotide formyltransferase/ IMP cyclohydrolase is enhanced by NPM-ALK: new insights in ALK-mediated pathogenesis and the treatment of ALCL. Am J Pathol 2000. Morris SW.69:2550–8. Aigner A. 46. 56. Fusion of the ALK gene to the clathrin heavy chain gene. Pulford K. and invasion properties of NIH3T3 cells. Cohn SL. Non-solid oncogenes in solid tumors: EML4-ALK fusion genes in lung cancer.CCR-08-2762 Molecular Pathways model for EML4-ALK-positive lung cancer. Bagatell R. the anaplastic lymphoma kinase. Boland JM.103: 9964–9.aacrjournals. Identification of NVP-TAE684.40:1152–8. Schmidt L.104:270–5. J Clin Oncol 2003. Galkin AV. Touriol C. Czubayko F. et al. Biochemistry 2009. Lawrence B. Kasprzycka M. MacLeod RA. et al.85: 863–75. Genome-wide analysis of neuroblastomas using high-density single nucleotide polymorphism arrays. Diskin S.11:145–56. et al. TPM3-ALK and TPM4-ALK oncogenes in inflammatory myofibroblastic tumors.67:4408–17. Oncogenic kinase signalling. 37. ALK mutants in the kinase domain exhibit altered kinase activity and differential sensitivity to small molecule ALK inhibitors. Marzec M. Cancer Res 2008. Ma Z. Boccalatte FE. 35. Cancer Res 2009.411:355–65. Nucleophosmin-anaplastic lymphoma kinase associated with anaplastic large-cell lymphoma activates the phosphatidylinositol 3-kinase/Akt antiapoptotic signaling pathway. Hogarty MD. Hu H. Genes Chromosomes Cancer 2002. Singh RR. Arango ME.105:19893–7. Nakaigawa N. CLTC. 42. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. Ouyang T. Neoplasia 2009.159:411–5. et al. Riganti C. Ohira M. Bai RY. a potent. et al.43:640–6. Am J Pathol 2005. Identification of novel fusion partners of ALK. Nakagawara A. Perez-Atayde A. in inflammatory myofibroblastic tumor. Davuluri Y. Erdogan S. Cho-Vega JH. Miething C.96:4319–27. Cell signaling by receptor tyrosine kinases. et al. Hibbard MK.
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