• What is ALK?
  • ALK in Neuroblastoma
  • ALK c.3452C>T (T1151M)
  • 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/neuroblastoma/alk/?tab=0 (Updated December 7).

Last Updated: December 7, 2015

ALK in Neuroblastoma

ALK mutations are found in 8–9% of neuroblastoma tumors (COSMIC; Weiser et al. 2011).

While ALK rearrangements predominate in other diseases, such as non-small cell lung cancer, point mutations predominate in neuroblastoma. The most common ALK mutations found in neuroblastoma are activating mutations (Carpenter and Mosse 2012; Schonherr et al. 2011). Activation of ALK contributes to cell growth, proliferation, survival, and migration (Carpenter and Mosse 2012). ALK activation—most often via germline R1275 mutations—has been identified as the primary cause of hereditary neuroblastoma in children (Carpenter and Mosse 2012; Mosse et al. 2008).

Several studies have contributed to the identification of ALK as a therapeutic target in neuroblastoma (Bresler et al. 2011; Chen et al. 2008; George et al. 2008; Janoueix-Lerosey et al. 2008; Schonherr et al. 2011). Both crizotinib and NVP-TAE684 have been explored in preclinical studies as potential therapies, and clinical trials of crizotinib in neuroblastoma are underway.


Table 2. Frequencies of Specific Mutations.
Gene Exon Amino Acid Position Amino Acid Change Nucleotide Change Frequency Among ALK-Mutated Neuroblastoma (COSMIC)
ALK 20 D1091 D1091N c.3271G>A 2%
22 T1151 T1151M c.3452C>T 1.5%
I1171 I1171N c.3512T>A 1.5%
23 F1174 F1174C c.3521T>G 4%
F1174I c.3520T>A 1.5%
F1174L c.3522C>A 37%
F1174V c.3520T>G 2%
24 F1245 F1245C c.3734T>G 1.5%
F1245L c.3735C>G 1.5%
F1245V c.3733T>G 3%
25 R1275 R1275Q c.3824G>A 33%
Y1278 Y1278S c.3833A>C​ 1.5% ​

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

Suggested Citation: Borinstein, S., V. Brown. 2015. ALK in Neuroblastoma. My Cancer Genome https://www.padiracinnovation.org/content/disease/neuroblastoma/alk/ (Updated February 18).

Last Updated: February 18, 2015

ALK c.3452C>T (T1151M) Mutation in Neuroblastoma

Properties
Location of Mutation Exon 22
Frequency of ALK mutations in neuroblastoma 8-9% (COSMIC​Weiser et al. 2011​)
Frequency of T1151M mutation among ALK-mutated neuroblastomas 1.5% (COSMIC)
Implications for Targeted Therapeutics
Response to crizotinib Unknown at this timea
Response to other ALK inhibitors Unknown at this timeb

The T1151M mutation results in an amino acid substitution at position 1151 in ALK, from a threonine (T) to a methionine (M).

a Clinical trials investigating crizotinib in neuroblastoma are underway. Preclinical studies have shown that R1275Q and wild type ALK amplified cell lines are sensitive to crizotinib (Bresler et al. 2011; Schonherr et al. 2011). F1174L cell lines are less sensitive than R1275Q cell lines to crizotinib, but they are still more sensitive than non-amplified wild type ALK cell lines (Bresler et al. 2011; Schonherr et al. 2011).

b The efficacy of ALK inhibitors other than crizotinib in neuroblastoma has been studied only in preclinical models thus far.

​​

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

Suggested Citation: Borinstein, S., V. Brown. 2015. ALK c.3452C>T (T1151M) Mutation in Neuroblastoma. My Cancer Genome https://www.padiracinnovation.org/content/disease/neuroblastoma/alk/174/ (Updated February 18).

Last Updated: February 18, 2015

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