• What is ALK?
  • ALK in Anaplastic Large Cell Lymphoma
  • ALK Fusions
  • Clinical Trials

ALK

The anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that is aberrant in a variety of malignancies. For example, activating missense mutations within full length ALK are found in a subset of neuroblastomas (Chen et al. 2008; George et al. 2008; Janoueix-Lerosey et al. 2008; Mosse et al. 2008). By contrast, ALK fusions are found in anaplastic large cell lymphoma (e.g., NPM-ALK; Morris et al. 1994), colorectal cancer (Lin et al. 2009​Lipson et al. 2012), inflammatory myofibroblastic tumor (IMT; Lawrence et al. 2000) non-small cell lung cancer (NSCLC; Choi et al. 2008; Koivunen et al. 2008; Rikova et al. 2007; Soda et al. 2007; Takeuchi et al. 2009), and ovarian cancer (Ren et al. 2012). All ALK fusions contain the entire ALK tyrosine kinase domain. To date, those tested biologically possess oncogenic activity in vitro and in vivo (Choi et al. 2008; Morris et al. 1994; Soda et al. 2007; Takeuchi et al. 2009). ALK fusions and copy number gains have been observed in renal cell carcinoma (Debelenko et al. 2011; Sukov et al. 2012). Finally, ALK copy number and protein expression aberrations have also been observed in rhabdomyosarcoma (van Gaal et al. 2012).

The various N-terminal fusion partners promote dimerization and therefore constitutive kinase activity (for review, see Mosse, Wood, and Maris 2009). Signaling downstream of ALK fusions results in activation of cellular pathways known to be involved in cell growth and cell proliferation (Figure 1).

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Figure 1.
Schematic representation of ALK fusions. "X" represents the various fusion partners that have been described. Dimerization of the ALK fusion mediated by the fusion partner ("X"), results in constitutive activation of the ALK tyrosine kinase. ALK signaling results in pro-growth and anti-apoptosis.

Related Pathways

Contributors: Christine M. Lovly, M.D., Ph.D., Leora Horn, M.D., M.Sc., William Pao, M.D., Ph.D. (through April 2014)

Suggested Citation: Lovly, C., L. Horn, W. Pao. 2015. ALK. My Cancer Genome https://www.padiracinnovation.org/content/disease/anaplastic-large-cell-lymphoma/alk/?tab=0 (Updated December 7).

Last Updated: December 7, 2015

ALK in Anaplastic Large Cell Lymphoma

ALK is expressed in 50–85% of ALCLs (Merkel et al. 2011). ). In 72–85% of these ALK-positive ALCLs, a translocation results in ALK fusions with NPM1; ALK fusion partners that have been found in the remaining 15–28% include TPM3, TPM4, TFG, ATIC, CLTC, MSN, MYH9, and ALO17 (RNF213; Damm-Welk et al. 2009; Falini and Martelli 2009; Moritake et al. 2011; Stein et al. 2000; Tort et al. 2001).

ALK positive ALCL has a better prognosis than ALK negative ALCL, and it is diagnosed more frequently in younger patients (Ferreri et al. 2012; Merkel et al. 2011). Use of ALK inhibitors such as crizotinib in the treatment of ALCL is being investigated.

Contributors: Valerie Brown, M.D., Ph.D., Scott C. Borinstein, M.D., Ph.D., Debra Friedman, M.D.

Suggested Citation: Brown, V., S. Borinstein, D. Friedman. 2013. ALK in Anaplastic Large Cell Lymphoma. My Cancer Genome https://www.padiracinnovation.org/content/disease/anaplastic-large-cell-lymphoma/alk/ (Updated March 6).

Last Updated: March 6, 2013

ALK Fusions in Anaplastic Large Cell Lymphoma

Properties
Location Chromosomal rearrangements involving the ALK gene on 2p23
Frequency of ALK fusions in ALCL 46-85% (Drexler et al. 2000; Merkel et al. 2011)
Implications for Targeted Therapeutics
Response to ALK inhibitors Unknown at this timea
Response to CD30 antibodies Unknown at this time
Response to PI3K/AKT/mTOR inhibitors Unknown at this time
Response to RAS inhibitors Unknown at this time
Response to JAK inhibitors Unknown at this time

a Clinical trials of crizotinib in ALK-positive ALCL are underway (Merkel et al. 2011). Preclinical studies demonstrated antitumor activity in ALCL cell lines with NPM-ALK fusions (Christensen et al. 2007​). In lung cancer, in the initial phase I trial, patients whose tumors harbored an ALK fusion displayed a 57% radiographic response rate to the dual ALK/MET tyrosine kinase inhibitor (TKI), crizotinib (Kwak et al. 2010). The probability of progression-free survival at 6 months was estimated to be 72%. Based on these initial results, an international phase III trial randomizing patients with advanced lung cancer harboring ALK fusions to crizotinib vs. standard chemotherapy after disease progression on first-line treatment was initiated and is now ongoing.

Contributors: Valerie Brown, M.D., Ph.D., Scott C. Borinstein, M.D., Ph.D., Debra Friedman, M.D.

Suggested Citation: Brown, V., S. Borinstein, D. Friedman. 2012. ALK Fusions in Anaplastic Large Cell Lymphoma. My Cancer Genome https://www.padiracinnovation.org/content/disease/anaplastic-large-cell-lymphoma/alk/66/ (Updated November 12).

Last Updated: November 12, 2012

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