ALK Inhibitors: Moving Rapidly From Discovery to Clinical Approval and Beyond

Jane de Lartigue, PhD
Published: Monday, Aug 27, 2012

ALK Action in Lung Cancer

ALK gene 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).

The dizzying pace continues as the molecular mechanisms of resistance to crizotinib have already begun to be unraveled and a second generation of ALK inhibitors is under development to overcome these issues. The recent identification of ALK abnormalities in numerous other tumor types besides lung cancer has expanded the potential of these drugs for treating other challenging cancer types.

Defining ALK and its Role in Cancer

The ALK 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.

The ALK gene was first determined to be a cancer-causing oncogene in 1990. It is now understood that ALK becomes oncogenic in a number of different ways: via mutations in the ALK gene that alter its function, via overexpression of the ALK protein, or via fusion with other genes through a process known as chromosomal translocation. Aberrant expression of the ALK gene through any of these means causes a cell to become cancerous due to inappropriate activation of ALK signaling, driving many of the cancer hallmarks, including cell proliferation and survival, through activation of the downstream pathways mentioned previously.

Activating mutations in the ALK gene have been identified in patients with neuroblastoma, the most common childhood cancer; the majority of patients with familial neuroblastoma and around 10% of patients with sporadic neuroblastoma have ALK mutations, most of which are found in the tyrosine kinase domain. Most prolific is the F1174 mutation, which is also correlated with a significantly worse patient outcome.

ALK protein overexpression is also common in neuroblastoma patients, identified in around 90% of cases. The percentage of cells in a tumor sample that are positive for ALK protein expression has been shown to correlate with patient outcome; the higher the level of ALK overexpression, the worse patient overall survival and disease- free survival. Recent reports have suggested that ALK overexpression is also a common feature of inflammatory breast cancer (IBC), prompting clinicians to begin enrolling patients with IBC in a phase I ALK inhibitor trial.

illustration of gene translocation

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

The most common ALK 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 inversion) 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 (NPM) gene; NPM-ALK occurs in approximately 80% of cases of anaplastic large cell lymphoma (ALCL; the cancer type from which the ALK gene actually derives its name).


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