Novel Tumor-specific Mutations in Receptor Tyrosine Kinase Subdomain IX Significantly Reduce Extracellular Signal-regulated Kinase Activity.
OBJECTIVE
The identification of additional therapeutic targets by clinical molecular profiling is necessary to expand the range of molecular-targeted cancer therapeutics. This study aimed to identify novel functional tumor-specific single nucleotide variants (SNVs) in the kinase domain of receptor tyrosine kinases (RTKs), from whole-exome sequencing (WES) data.


METHODS
SNVs were selected from WES data of multiple cancer types using both cancer-related databases and the index reflecting molecular evolution. Immunoblotting and luciferase assay were performed to assess the function of selected SNVs.


RESULTS
Among the seven selected SNVs, two, namely neurotrophic receptor tyrosine kinase 1 (NTRK1) V710A and fms related tyrosine kinase 3 (FLT3) K868N, detected in kinase subdomain IX, were investigated. These SNVs inhibited the autophosphorylation of the respective RTKs, thereby reducing the activity of extracellular signal-regulated kinases.


CONCLUSIONS
RTK subdomain IX is a promising target for the molecular design of kinase inhibitors.
Drug Discovery and Development Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan.
Masakuni
M
Serizawa
Drug Discovery and Development Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan Region Resources Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan m.kusuhara@scchr.jp.
Masatoshi
M
Kusuhara
Cancer Diagnostics Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan.
Sumiko
S
Ohnami
Cancer Diagnostics Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan SRL, Inc., Tokyo, Japan.
Takeshi
T
Nagashima
Cancer Diagnostics Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan SRL, Inc., Tokyo, Japan.
Yuji
Y
Shimoda
Medical Genetics Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan.
Keiichi
K
Ohshima
Medical Genetics Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan.
Tohru
T
Mochizuki
Cancer Diagnostics Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan.
Kenichi
K
Urakami
Shizuoka Cancer Center Hospital and Research Institute, Shizuoka, Japan.
Ken
K
Yamaguchi
D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D058990:Molecular Targeted Therapy; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics*; D010766:Phosphorylation; D000072417:Protein Domains; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics*
D047428:Protein Kinase Inhibitors; D020794:Receptor Protein-Tyrosine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases
FLT3; NTRK1; kinase subdomain IX; molecular-targeted cancer therapeutics; receptor tyrosine kinase; whole-exome sequencing