Crizotinib

Brand Name: Xalkori

Crizotinib is used to treat non-small cell lung cancer, anaplastic large cell lymphoma, and inflammatory myofibroblastic tumor.1

How Does Crizotinib Work?

Tyrosine kinase uses ATP to attach a phosphate tag on other proteins in a process called phosphorylation. This results in the transmission of growth signals.

Cellular growth signals are often transmitted through a process called phosphorylation, in which an enzyme called tyrosine kinase attaches a phosphate tag to another protein. This phosphate tag is derived from a molecule called ATP.2

ALK protein on the surface of the cell.

ALK is a protein in the receptor tyrosine kinase family. This protein consists of a receptor domain outside the cell connected to a tyrosine kinase domain inside the cell.3

Monomeric ALK tyrosine kinase is inactive. Dimeric ALK tyrosine kinase is active.

The kinase domain of ALK is inactive by itself, but when two kinase domains come together to form a dimer, the kinase is activated. Active ALK kinases then phosphorylate itself and other proteins to transmit growth signals.4

Two ALK proteins are separated on the surface of the cell.

In normal conditions, ALK does not associate with each other and remains monomeric and inactive.4

Receptor binding to ALKAL2 and heparin results in ALK dimerization.

On the other hand, in the presence of a growth factor called ALKAL25, as well as a sugar chain called heparin6, the structure of the receptor domain of ALK changes in a way that facilitates dimerization of ALK.7

Active ALK transmits growth signal through phosphorylation.

This brings two kinase domains of ALK together and activates them to transmit growth signals through phosphorylation. Of note, because the dimerization of ALK requires the binding of growth factors, growth signaling transmitted by ALK is controllable; when cell growth is no longer necessary, growth factor production ceases, which returns ALK to its inactive monomeric form.4

Mutated ALK with its receptor domain replaced with EML4.

In some types of cancer, a mutation in the ALK gene results in the replacement of the receptor domain of ALK with a part of another protein called EML4. This results in an EML4-ALK fusion protein.8

Three EML4-ALK fusion proteins bind together to form an active trimer.

EML4 are intrinsically able to trimerize, so the kinases of EML4-ALK fusion proteins are constitutively active.9

Growth signal level ranges from no signal from inactive ALK, to controlled signal from active ALK dimer, to cancerous signal from EML4-ALK fusion protein.

This leads to an uncontrolled phosphorylation by EML4-ALK fusion proteins, and the resulting surge in growth signals leads to cancer proliferation.9

Crizotinib blocks the ATP-binding site of EML4-ALK and stops growth signal transmission.

Crizotinib is a type of drug called kinase inhibitors. It blocks the kinase domain of EML4-ALK fusion protein from accessing the ATP required for phosphorylation.10 This turns off the growth signal, and as a result, cancer growth is halted.

References

1. XALKORI - Label. U.S. Food and Drug Administration (2023).

2. Hubbard, S. R. & Till, J. H. Protein Tyrosine Kinase Structure and Function. Annual Review of Biochemistry 69, 373-398 (2000).

3. Iwahara, T. et al. Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system. Oncogene 14, 439-449 (1997).

4. Hallberg, B. & Palmer, R. H. Mechanistic insight into ALK receptor tyrosine kinase in human cancer biology. Nature Reviews Cancer 13, 685-700 (2013).

5. Reshetnyak, A. V., Murray, P. B., Shi, X. & Schlessinger, J. Augmentor α and β (FAM150) are ligands of the receptor tyrosine kinases ALK and LTK: Hierarchy and specificity of ligand-receptor interactions. Proceedings of the National Academy of Sciences of the United States of America 112, 15862-15867 (2015).

6. Murray, P. B. et al. Heparin is an activating ligand of the orphan receptor tyrosine kinase ALK. Science Signaling 8(360), ra6 (2015).

7. Reshetnyak, A. V. et al. Mechanism for the activation of the anaplastic lymphoma kinase receptor. Nature 600, 153-157 (2021).

8. Soda, M. et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448, 561-566 (2007).

9. Richards, M. W. et al. Microtubule association of EML proteins and the EML4-ALK variant 3 oncoprotein require an N-terminal trimerization domain. Biochemical Journal 467, 529-536 (2015).

10. Christensen, J. G. et al. Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma. Molecular Cancer Therapeutics 6, 3314-3322 (2007).