Crizotinib (Xalkori) Mechanism of Action and ALK Fusion Genes In NSCLC

Get New Treatments Alerts:

Crizotinib bound to ATP binding pockets in ALK protein.

Pfizer’s Xalkori (Crizotinib) has been found to increase progression free survival in lung cancer patients with ALK mutations who have been previously treated. Crizotinib was approved by the FDA in August 2011 for treating ALK positive NSCLC. Pfizer continues clinical trials on Crizotinib and these results are from the Phase 3 PROFILE 1007 study.

In order to understand mechanism of action of crizotinib and its specificity for ALK mutations, we need to first understand ALK fusion genes and proteins.

It was in the year 2007 that EML4-ALK fusion gene was identified as tumorigenic in NSCLC.
EML4-ALK is an inversion, this means that EML4 gene intron 13 links to intron 19 of ALK gene.
EML4-ALK gene is 3926 base pairs and codes for a protein of 1059 amino acids.
Incorporation of EML4-ALK gene into experimental mouse saw tumor formation.
ALK inhibitors like crizotinib reduced tumor size, and prolonged survival.
Some facts:
- The exact intracellular signaling pathway by which EML4-ALk fusion proteins cause tumor growth and development has not been fully characterized.
- The physiological function of ALK is not known.
- There is scientific evidence that ALK gene plays a role in nervous system development.
- Expression of ALK protein has been observed in some cells of the central nervous system.

Mechanism of Action of Crizotinib

Crizotinib (Xalkori) is an orally active inhibitor of ALK and c-Met receptor tyrosine kinase.
Crizotinib belongs to 3-benzyloxy-2-aminopyridine series of kinase inhibitors.
The drug is very selective for ALK and c-Met kinases with 50% inhibitory concentration values for ALK and c-Met, when compared to values that were 20 fold higher for other kinases.
Crizotinib binds to the adenosine triphosphate (ATP) binding site of the ALK enzyme.
This prevents autophosphorylation of ATP which is required for enzyme activation.

Lung cancer is among the most common cancers and cause of cancer related deaths across the world. About 85% of lung cancers are non-small cell lung cancer (NSCLC) and most of the patients are diagnosed at advanced stages. The 5 year survival for patients in the USA with NSCLC is about 16%. Current treatments for NSCLC focus on prolonging survival and are rarely curative.