ALK Gene Mutation and Cancer Treatment

The ALK gene codes for a protein called anaplastic lymphoma kinase. This protein is localized to the membrane of cells, and is thought to be involved in the development and maintenance of the central and peripheral nervous systems. The exact function of the protein is currently not well understood, however. The gene is located on chromosome 2.

Mutations of the ALK gene are caused by gene rearrangement, in which sections of the gene become arranged in an abnormal sequence during the DNA replication phase of cell division. The abnormal ALK protein is unable to embed in the cell membrane and cannot perform its normal function. Through an unknown mechanism, cells with this mutation can no longer control their growth cycle, leading to uncontrolled proliferation and the potential for cancer.

Studies have shown that the anaplastic lymphoma kinase protein is expressed mostly in central nervous system tissues, particularly in certain regions of the brain. The localization of to nervous system tissues means that malignant transformation of the protein is most likely to affect these tissues.

Neuroblastoma is a type of cancer that affects nervous tissue, including that of the spinal cord as well as the brain, and other tissues such as the adrenal glands. Childhood neuroblastoma is a genetically-inherited form of the cancer which accounts for a significant proportion of childhood deaths from cancer.

Several distinct genetic mutations in the ALK gene have been discovered to cause childhood neuroblastoma, as well as some cases of spontaneous neuroblastoma. The existence of known mutations means that targeted therapy might be developed to treat neuroblastoma caused by ALK mutations.

In addition, with the discovery of these mutations it became possible to screen for the mutated gene where a family history of the cancer exists.

Childhood neuroblastoma is not the only cancer in which the ALK gene is implicated. Rearrangements of the ALK gene are also known to exist in other types of cancer, including certain types of nonsmall-cell lung cancer (NSCLC). This means that cancer therapy targeted towards the ALK gene might be of significant benefit in cases of this type of cancer.

A phase 1 clinical trial begun in 2006 by Pfizer has demonstrated that an oral ALK inhibitor might be an effective treatment for NSCLC in up to 65% of cases. It should be noted, however, that the drug is not necessarily curative, as there is the possibility that the cancer might become resistant to the drug.

Atlas of Genetics and Cytogenetics in Oncology and Haematology: ALK (anaplastic lymphoma receptor tyrosine kinase)

Mossé Yaël P., et. al. Identification of ALK as a major familial neuroblastoma predisposition gene. Nature 455, 930-935 (16 October 2008).

Nelson, Roxanne. ALK Inhibitors: Possible New Treatment for Lung Cancer