ALK Action in Lung Cancer
In non-small cell lung cancer, the translocation of the ALK gene with EML4 results in a fusion protein that activates signaling pathways, enabling the survival and proliferation of cancer cells.
Adapted from Shaw AT, Solomon B. Targeting anaplastic lymphoma kinase in lung cancer [published online ahead of print February 2, 2011]. Clin Cancer Res. 2011;17(8):2081-2086. doi: 10.1158/1078- 0432.CCR-10-1591.
In 2007, rearrangements of the anaplastic lymphoma kinase (ALK
) gene were identified in patients with lung cancer. There has been stunning progress in the intervening years as these preclinical findings were translated into the availability of an FDA-approved therapeutic ALK inhibitor, crizotinib (Xalkori).
and its Role in Cancer
gene encodes a receptor tyrosine kinase (RTK) that sits upstream of and transmits signals through a number of other important kinases, including phosphatidylinositol- 3-kinase (PI3K) and Janus kinase (JAK). Under normal circumstances, the ALK receptor is expressed predominantly in the central nervous system (CNS), small intestine, and testes. Its normal function in humans is not fully understood as yet, though it is believed to play an important role in the development of the brain.
This illustration depicts the components of a chromosome and a gene, as well as the process of translocation, which plays a role in some ALK-driven cancers.
Illustration courtesy of The Cancer Genome Atlas/National Cancer Institute
abnormality found in cancer is chromosomal translocation. Translocation leads to the rearrangement of genetic information with a chromosome when parts of that chromosome break off and fuse with other chromosomes, or flip around (a process called
) and join with a different part of the same chromosome. This results in parts of one gene becoming fused to parts of a completely different gene, and the expression of fusion proteins. The most common fusion partner for ALK is the nucleophosmin (
occurs in approximately 80% of cases of anaplastic large cell lymphoma (ALCL; the cancer type from which the
gene actually derives its name).