Related Experiment Video

Updated: Feb 14, 2026

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
12:40

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors

Published on: December 7, 2014

15.3K

A secondary RET mutation in the activation loop conferring resistance to vandetanib

Takashi Nakaoku1, Takashi Kohno2,3, Mitsugu Araki4,5

  • 1Division of Genome Biology, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 1040045, Japan.

Nature Communications
|February 14, 2018
PubMed

Insights

A patient with lung adenocarcinoma developed resistance to vandetanib due to a RET kinase mutation. This S904F mutation increases kinase activity, leading to drug resistance via allosteric effects.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Vandetanib is a type I RET kinase inhibitor used for metastatic lung adenocarcinoma.
  • CCDC6-RET fusions are common drivers in certain lung cancers, initially responsive to RET inhibitors.

Observation:

  • A patient with a CCDC6-RET fusion-positive tumor developed acquired resistance to vandetanib.
  • The resistant tumor acquired a secondary RET kinase domain mutation, S904F (serine-to-phenylalanine at codon 904).

Findings:

  • The S904F mutation increases RET kinase's ATP affinity and autophosphorylation activity.
  • In vitro thermal shift assays showed reduced interaction between vandetanib and the S904F mutant.
  • Crystal structure of the S904F mutant revealed a stabilized active conformer, enhancing basal kinase activity.

Implications:

  • Missense mutations in the RET kinase activation loop can confer drug resistance.
  • These mutations increase kinase activity through allosteric effects, impacting therapeutic strategies.
  • Understanding resistance mechanisms is crucial for developing next-generation RET inhibitors.

More Related Videos

Measuring Microbial Mutation Rates with the Fluctuation Assay07:44

Measuring Microbial Mutation Rates with the Fluctuation Assay

Published on: November 28, 2019

25.0K
Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms08:46

Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms

Published on: December 9, 2015

11.2K

Related Concept Videos

Secondary Active Transport01:55

Secondary Active Transport

One example of how cells use the energy contained in electrochemical gradients is demonstrated by glucose transport into cells. The ion vital to this process is sodium (Na+), which is typically present in higher concentrations extracellularly than in the cytosol. Such a concentration difference is due, in part, to the action of an enzyme “pump” embedded in the cellular membrane that actively expels Na+ from a cell. Importantly, as this pump contributes to the high concentration of...
138.3K
Secondary Active Transport01:32

Secondary Active Transport

One example of how cells use the energy contained in electrochemical gradients is demonstrated by glucose transport into cells. The ion vital to this process is sodium (Na+), which is typically present in higher concentrations extracellularly than in the cytosol. Such a concentration difference is due, in part, to the action of an enzyme "pump" embedded in the cellular membrane that actively expels Na+ from a cell. Importantly, as this pump contributes to the high concentration of...
9.8K
Mutations01:39

Mutations

Overview
94.7K
Mutations01:35

Mutations

Mutations are changes in the sequence of DNA. These changes can occur spontaneously or they can be induced by exposure to environmental factors. Mutations can be characterized in a number of different ways: whether and how they alter the amino acid sequence of the protein, whether they occur over a small or large area of DNA, and whether they occur in somatic cells or germline cells.
Chromosomal Alterations Are Large-Scale Mutations
While point mutations are changes in a single nucleotide in...
44.7K
Viral Mutations00:36

Viral Mutations

A mutation is a change in the sequence of bases of DNA or RNA in a genome. Some mutations occur during replication of the genome due to errors made by the polymerase enzymes that replicate DNA or RNA. Unlike DNA polymerase, RNA polymerase is prone to errors because it is not capable of “proofreading” its work. Viruses with RNA-based genomes, like HIV, therefore accrue mutations faster than viruses with DNA-based genomes. Because mutation and recombination provide the raw material...
40.0K
Primary and Secondary Growth in Roots and Shoots03:02

Primary and Secondary Growth in Roots and Shoots

Vascular plants, which account for over 90% of the Earth’s vegetation, all undergo primary growth—which lengthens roots and shoots. Many land plants, notably woody plants, also undergo secondary growth—which thickens roots and shoots.
60.7K