• What is ALK?
  • ALK in Inflammatory Myofibroblastic Tumor
  • 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).

alk.png

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/inflammatory-myofibroblastic-tumor/alk/?tab=0 (Updated December 7).

Last Updated: December 7, 2015

ALK in Inflammatory Myofibroblastic Tumor

50-60% of IMTs carry translocations involving the ALK gene on chromosome 2p23 (Coffin, Hornick, and Fletcher 2007; Saab et al. 2011). These translocations juxtapose portions of the ALK gene to various 5’ translocation partners, including RANBP2, TPM3, TPM4, ATIC, CLTC, CARS, and SEC31L1 (COSMIC). The result is constitutive activation of the ALK tyrosine kinase. Clinically, the presence of ALK expression is determined by immunohistochemistry (IHC), and the patterning of staining may correlate with the specific gene fusion (Gleason and Hornick 2008). To date, there are limited data to suggest that the presence of a specific ALK fusion type affects prognosis (Marino-Enriquez et al. 2011).

Use of the ALK inhibitor crizotinib in IMT was first reported in 2010. In this study, the patient with ALK-positive IMT responded to crizotinib, while the patient with ALK-negative IMT did not (Butrynski et al. 2010). At this time, phase 1 and 2 trials of crizotinib and other ALK inhibitors in IMT are underway.

Contributors: Christine M. Lovly, M.D., Ph.D., Valerie Brown, M.D., Ph.D., Scott C. Borinstein, M.D., Ph.D., Debra Friedman, M.D., Cheryl M. Coffin, M.D.

Suggested Citation: Lovly, C., V. Brown, S. Borinstein, D. Friedman, C. Coffin. 2014. ALK in Inflammatory Myofibroblastic Tumor. My Cancer Genome https://www.padiracinnovation.org/content/disease/inflammatory-myofibroblastic-tumor/alk/ (Updated August 7).

Last Updated: August 7, 2014

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