The anaplastic lymphoma kinase (ALK) has emerged as a potentially relevant biomarker and therapeutic target in pediatric solid and hematologic malignancies. It is a receptor tyrosine kinase (RTK) that is known to be activated either by point mutations or by chromosomal translocations. These genetic alterations act as oncogenic drivers and promote constitutive, ligand-independent activation of this RTK. Recurrent activating point mutations are seen within kinase domain in both the hereditary and sporadic form of neuroblastoma cases (7-10%). According to some studies, the presence of an ALK aberration could be a biomarker of aggressive disease and inferior clinical outcome. Clinical trials of crizotinib in neuroblastoma are underway. The R1275Q mutation is most common variant among ALK-mutated neuroblastomas (33%), and is found in both sporadic and familial cases. The R1275 amino acid substitution lies within the activation loop and causes constitutive ligand-independent activation of this RTK. Both preclinical and clinical studies suggest that this mutation could be sensitive to ALK inhibition.

The anaplastic lymphoma kinase (ALK) has emerged as a potentially relevant biomarker and therapeutic target in a variety of solid and hematologic malignancies. It is a receptor tyrosine kinase (RTK) that is known to be activated either by point mutations or by chromosomal translocations. These genetic alterations act as oncogenic drivers and promote constitutive, ligand-independent activation of this RTK. Approximately 3-7% of non-small cell lung cancers (NSCLC) harbor ALK fusions/rearrangements. This fusion oncogene rearrangement is transforming both in vitro and in vivo and defines a distinct clinicopathologic subset of NSCLC that are highly sensitive to therapy with ALK-targeted inhibitors. While crizotinib is highly active in patients with ALK-positive NSCLC, patients have been shown to invariably develop resistance to this drug. In approximately one-third of resistant cases, tumors can acquire a secondary mutation within the ALK tyrosine kinase domain. ALK F1174 variant is a somatic mutation in the ALK kinase domain and has been detected in neuroblastomas. It has a transforming activity in vitro and in vivo, and may cause resistance to crizotinib as well as second generation ALK inhibitors such as ceritinib.

The anaplastic lymphoma kinase (ALK) has emerged as a potentially relevant biomarker and therapeutic target in a variety of solid and hematologic malignancies. It is a receptor tyrosine kinase (RTK) that is known to be activated either by point mutations or by chromosomal translocations. These genetic alterations act as oncogenic drivers, promoting constitutive, ligand-independent activation of this RTK. Approximately 3-7% of non-small cell lung cancers (NSCLC) harbor ALK fusions/rearrangements. ALK fusion oncogenes are transforming both in vitro and in vivo, defining a distinct clinicopathologic subset of NSCLC that are highly sensitive to therapy with ALK-targeted inhibitors. While crizotinib (ALK/MET TKI) is highly active in patients with ALK-positive NSCLC, patients have been shown to invariably develop resistance to this drug. In approximately one-third of resistant cases, tumors can acquire a secondary mutation within the ALK tyrosine kinase domain. L1196 is present in the gatekeeper position at the bottom of the ATP-binding pocket of the protein. Gatekeeper genetic alterations seem to confer TKI resistance in oncogenic tyrosine kinases. L1196M mutant confers high-level resistance to crizotinib, but has been shown to be sensitive to ceretinib.

The anaplastic lymphoma kinase (ALK) has emerged as a potentially relevant biomarker and therapeutic target in a variety of solid and hematologic malignancies. It is a receptor tyrosine kinase (RTK) that is known to be activated either by point mutations or by chromosomal translocations. These genetic alterations act as oncogenic drivers, promoting constitutive, ligand-independent activation of this RTK. Approximately 3-7% of non-small cell lung cancers (NSCLC) harbor ALK fusions/rearrangements. ALK fusion oncogenes are transforming both in vitro and in vivo, defining a distinct clinicopathologic subset of NSCLC that are highly sensitive to therapy with ALK-targeted inhibitors. While crizotinib (ALK/MET TKI) is highly active in patients with ALK-positive NSCLC, patients have been shown to invariably develop resistance to this drug. In approximately one-third of resistant cases, tumors can acquire a secondary mutation within the ALK tyrosine kinase domain. ALK G1202R is postulated to be in the solvent-exposed region abutting the crizotinib-binding site, likely diminishing the binding affinity of crizotinib and other ALK inhibitors to the mutant ALK. G1202R has been shown to cause resistance to crizotinib as well as second generation ALK inhibitors (ceritinib, alectinib).

This gene is a known cancer gene.

This gene is a known cancer gene.