The EML4-ALK oncogene: targeting an essential growth driver in human cancer.

Abstract

Targeting of essential growth drivers represents an ideal approach to cancer treatment. To identify such molecules in clinical specimens, we developed a highly sensitive functional screening system based on the preparation of retroviral cDNA expression libraries. By screening such a library of lung adenocarcinoma with a focus formation assay, we discovered the EML4-ALK fusion-type oncogene. A small chromosomal inversion thus leads to fusion of the amino-terminal portion of the microtubule-associated protein EML4 to the intracellular kinase domain of ALK, a receptor-type protein tyrosine kinase. Constitutive dimerization of EML4-ALK mediated by a dimerization motif of EML4 results in kinase activation. Specific inhibitors of the kinase activity of ALK have been developed as therapeutic drugs for EML4-ALK-positive lung cancer, three of which (crizotinib, ceritinib, and alectinib) have already been approved for clinical use. An overall clinical response rate of 93.5% for alectinib has shown that agents that target essential growth drivers can become magic bullets for cancer treatment.

• Authors: Hiroyuki Mano
• Journal: Proceedings of the Japan Academy. Series B, Physical and biological sciences (Proc Jpn Acad Ser B Phys Biol Sci) Vol. 91 Issue 5 Pg. 193-201 ( 2015) ISSN: 1349-2896 [Electronic] Japan
• PMID: 25971657 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• EML4-ALK fusion protein, human
• Oncogene Proteins, Fusion
• Protein Kinase Inhibitors

Topics

• Animals
• Cell Proliferation (drug effects)
• Humans
• Molecular Targeted Therapy (methods)
• Neoplasms (drug therapy, genetics, metabolism, pathology)
• Oncogene Proteins, Fusion (genetics, metabolism)
• Oncogenes
• Protein Kinase Inhibitors (pharmacology, therapeutic use)