• What is ALK?
  • ALK in Rhabdomyosarcoma
  • ALK c.3673G>A (D1225N)
  • Clinical Trials


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).


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/rhabdomyosarcoma/alk/?tab=0 (Updated December 7).

Last Updated: December 7, 2015

ALK in Rhabdomyosarcoma

ALK expression is found in 15-32% of embryonal rhabdomyosarcomas and 45-81% of alveolar rhabdomyosarcomas (Corao et al. 2009; Pillay, Govender, and Chetty 2002; van Gaal et al. 2012). Because ALK is normally only expressed in embryos and neonatal brain tissue, any expression after birth in any tissue other than brain tissue is abnormal. Whole exon deletions in ALK were observed in 21% of embryonal rhabdomyosarcomas and 10% of alveolar rhabdomyosarcomas (van Gaal et al. 2012). ALK mutations in rhabdomyosarcoma are uncommon, although one has been observed: D1225N (Shukla et al. 2012; van Gaal et al. 2012).

Because mutations known to give rise to activated forms of ALK have not yet been observed in ALK, it is unknown whether ALK inhibitors may be effective in rhabdomyosarcoma (van Gaal et al. 2012). Further preclinical and clinical research is needed.


Contributors: Scott C. Borinstein, M.D., Ph.D.

Suggested Citation: Borinstein, S. 2012. ALK in Rhabdomyosarcoma. My Cancer Genome https://www.padiracinnovation.org/content/disease/rhabdomyosarcoma/alk/ (Updated August 13).

Last Updated: August 13, 2012

ALK c.3673G>A (D1225N) Mutation in Rhabdomyosarcoma

Location of Mutation Exon 24
Frequency of D1225N in embryonal rhabdomyosarcoma Not observed (van Gaal et al. 2012)
Frequency of D1225N in alveolar rhabdomyosarcoma Observed in one case (van Gaal et al. 2012)
Implications for Targeted Therapeutics
Response to ALK inhibitors Unknown at this time

The D1225N mutation results in an amino acid substitution at position 1225 in ALK, from an aspartic acid (D) to an asparagine (N). The effects of this mutation are not known.

Contributors: Scott C. Borinstein, M.D., Ph.D.

Suggested Citation: Borinstein, S. 2012. ALK c.3673G>A (D1225N) Mutation in Rhabdomyosarcoma. My Cancer Genome https://www.padiracinnovation.org/content/disease/rhabdomyosarcoma/alk/187/ (Updated August 13).

Last Updated: August 13, 2012

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