Resistance to vandetanib through allosteric effects

Elucidation of a drug resistance mechanism by nationwide genome screening

A collaborative research endeavor including Kyoto University, University of Tokyo, the National Cancer Center, RIKEN, the Francis Crick Institute, has elucidated a novel mechanism underlying acquired resistance to the RET tyrosine kinase inhibitor in lung cancer. The findings were published in the journal Nature Communications .

Lung adenocarcinoma is the most common type of lung cancer in the world, and 1-2% of patients present oncogenic fusions of the RET kinase gene. Fortunately, treatments are available in the form of RET tyrosine kinase inhibitors, or TKIs, such as vandetanib.

In the study, researchers report the first case of a RET mutation causing a resistance to vandetanib treatments. While the patient initially responded to treatment, the tumor acquired a secondary mutation that resulted in enhanced kinase activity.

The team found that that acquired resistance was the result of a serine-to-phenylalanine substitution at codon 904 in the activation loop of the RET kinase gene. The mutation conferred resistance to vandetanib by increasing the ATP affinity and autophosphorylation activity of RET kinase.

Furthermore, a thermal shift assay and molecular dynamics simulation showed that the mutant had lower thermal stabilization, and reduced interaction with the drug.

Analysis of the mutant's crystal structure revealed a small hydrophobic core around F904. This structure is likely to enhance basal kinase activity by stabilizing its conformation.

These findings indicate that missense mutations of the kinase domain are able to increase kinase activity and confer drug resistance.

As cancer studies progress, the underlying cause of how some cancers become resistant to drug treatments are becoming better understood. Using crystallography and biophysical studies, the team hopes to uncover more of these changes, as well as the precise mechanisms underlying these structural effects.