Mutations in the c-Kit gene disrupt mitogen-activated protein kinase signaling during tumor development in adenoid cystic carcinoma of the salivary glands

Osamu Tetsu, Janyaporn Phuchareon, Annie Chou, Darren P. Cox, David W Eisele, Richard C K Jordan

Research output: Contribution to journalArticle

Abstract

The Ras/mitogen-activated protein kinase (MAPK) pathway is considered to be a positive regulator of tumor initiation, progression, and maintenance. This study reports an opposite finding: we have found strong evidence that the MAPK pathway is inhibited in a subset of adenoid cystic carcinomas (ACCs) of the salivary glands. ACC tumors consistently overexpress the receptor tyrosine kinase (RTK) c-Kit, which has been considered a therapeutic target. We performed mutational analysis of the c-Kit gene (KIT) in 17 cases of ACC and found that 2 cases of ACC had distinct missense mutations in KIT at both the genomic DNA and messenger RNA levels. These mutations caused G664R and R796G amino acid substitutions in the kinase domains. Surprisingly, the mutations were functionally inactive in cultured cells. We observed a significant reduction of MAPK (ERK1/2) activity in tumor cells, as assessed by immunohistochemistry. We performed further mutational analysis of the downstream effectors in the c-Kit pathway in the genes HRAS, KRAS, NRAS, BRAF, PIK3CA, and PTEN. This analysis revealed that two ACC tumors without KIT mutations had missense mutations in either KRAS or BRAF, causing S17N K-Ras and V590I B-Raf mutants, respectively. Our functional analysis showed that proteins with these mutations were also inactive in cultured cells. This is the first time that MAPK activity from the RTK signaling has been shown to be inhibited by gene mutations during tumor development. Because ACC seems to proliferate despite inactivation of the c-Kit signaling pathway, we suggest that selective inhibition of c-Kit is probably not a suitable treatment strategy for ACC.

Original languageEnglish (US)
Pages (from-to)708-717
Number of pages10
JournalNeoplasia
Volume12
Issue number9
DOIs
StatePublished - Sep 2010
Externally publishedYes

Fingerprint

Adenoid Cystic Carcinoma
Mitogen-Activated Protein Kinases
Salivary Glands
Mutation
Genes
Neoplasms
Receptor Protein-Tyrosine Kinases
Missense Mutation
Cultured Cells
Mitogen-Activated Protein Kinase 1
Amino Acid Substitution
Phosphotransferases
Immunohistochemistry
Maintenance
Messenger RNA
DNA
Therapeutics

ASJC Scopus subject areas

  • Cancer Research

Cite this

Mutations in the c-Kit gene disrupt mitogen-activated protein kinase signaling during tumor development in adenoid cystic carcinoma of the salivary glands. / Tetsu, Osamu; Phuchareon, Janyaporn; Chou, Annie; Cox, Darren P.; Eisele, David W; Jordan, Richard C K.

In: Neoplasia, Vol. 12, No. 9, 09.2010, p. 708-717.

Research output: Contribution to journalArticle

Tetsu, Osamu ; Phuchareon, Janyaporn ; Chou, Annie ; Cox, Darren P. ; Eisele, David W ; Jordan, Richard C K. / Mutations in the c-Kit gene disrupt mitogen-activated protein kinase signaling during tumor development in adenoid cystic carcinoma of the salivary glands. In: Neoplasia. 2010 ; Vol. 12, No. 9. pp. 708-717.
@article{a9017c6b5fa94d469498325137ac2cec,
title = "Mutations in the c-Kit gene disrupt mitogen-activated protein kinase signaling during tumor development in adenoid cystic carcinoma of the salivary glands",
abstract = "The Ras/mitogen-activated protein kinase (MAPK) pathway is considered to be a positive regulator of tumor initiation, progression, and maintenance. This study reports an opposite finding: we have found strong evidence that the MAPK pathway is inhibited in a subset of adenoid cystic carcinomas (ACCs) of the salivary glands. ACC tumors consistently overexpress the receptor tyrosine kinase (RTK) c-Kit, which has been considered a therapeutic target. We performed mutational analysis of the c-Kit gene (KIT) in 17 cases of ACC and found that 2 cases of ACC had distinct missense mutations in KIT at both the genomic DNA and messenger RNA levels. These mutations caused G664R and R796G amino acid substitutions in the kinase domains. Surprisingly, the mutations were functionally inactive in cultured cells. We observed a significant reduction of MAPK (ERK1/2) activity in tumor cells, as assessed by immunohistochemistry. We performed further mutational analysis of the downstream effectors in the c-Kit pathway in the genes HRAS, KRAS, NRAS, BRAF, PIK3CA, and PTEN. This analysis revealed that two ACC tumors without KIT mutations had missense mutations in either KRAS or BRAF, causing S17N K-Ras and V590I B-Raf mutants, respectively. Our functional analysis showed that proteins with these mutations were also inactive in cultured cells. This is the first time that MAPK activity from the RTK signaling has been shown to be inhibited by gene mutations during tumor development. Because ACC seems to proliferate despite inactivation of the c-Kit signaling pathway, we suggest that selective inhibition of c-Kit is probably not a suitable treatment strategy for ACC.",
author = "Osamu Tetsu and Janyaporn Phuchareon and Annie Chou and Cox, {Darren P.} and Eisele, {David W} and Jordan, {Richard C K}",
year = "2010",
month = "9",
doi = "10.1593/neo.10356",
language = "English (US)",
volume = "12",
pages = "708--717",
journal = "Neoplasia",
issn = "1522-8002",
publisher = "Elsevier Inc.",
number = "9",

}

TY - JOUR

T1 - Mutations in the c-Kit gene disrupt mitogen-activated protein kinase signaling during tumor development in adenoid cystic carcinoma of the salivary glands

AU - Tetsu, Osamu

AU - Phuchareon, Janyaporn

AU - Chou, Annie

AU - Cox, Darren P.

AU - Eisele, David W

AU - Jordan, Richard C K

PY - 2010/9

Y1 - 2010/9

N2 - The Ras/mitogen-activated protein kinase (MAPK) pathway is considered to be a positive regulator of tumor initiation, progression, and maintenance. This study reports an opposite finding: we have found strong evidence that the MAPK pathway is inhibited in a subset of adenoid cystic carcinomas (ACCs) of the salivary glands. ACC tumors consistently overexpress the receptor tyrosine kinase (RTK) c-Kit, which has been considered a therapeutic target. We performed mutational analysis of the c-Kit gene (KIT) in 17 cases of ACC and found that 2 cases of ACC had distinct missense mutations in KIT at both the genomic DNA and messenger RNA levels. These mutations caused G664R and R796G amino acid substitutions in the kinase domains. Surprisingly, the mutations were functionally inactive in cultured cells. We observed a significant reduction of MAPK (ERK1/2) activity in tumor cells, as assessed by immunohistochemistry. We performed further mutational analysis of the downstream effectors in the c-Kit pathway in the genes HRAS, KRAS, NRAS, BRAF, PIK3CA, and PTEN. This analysis revealed that two ACC tumors without KIT mutations had missense mutations in either KRAS or BRAF, causing S17N K-Ras and V590I B-Raf mutants, respectively. Our functional analysis showed that proteins with these mutations were also inactive in cultured cells. This is the first time that MAPK activity from the RTK signaling has been shown to be inhibited by gene mutations during tumor development. Because ACC seems to proliferate despite inactivation of the c-Kit signaling pathway, we suggest that selective inhibition of c-Kit is probably not a suitable treatment strategy for ACC.

AB - The Ras/mitogen-activated protein kinase (MAPK) pathway is considered to be a positive regulator of tumor initiation, progression, and maintenance. This study reports an opposite finding: we have found strong evidence that the MAPK pathway is inhibited in a subset of adenoid cystic carcinomas (ACCs) of the salivary glands. ACC tumors consistently overexpress the receptor tyrosine kinase (RTK) c-Kit, which has been considered a therapeutic target. We performed mutational analysis of the c-Kit gene (KIT) in 17 cases of ACC and found that 2 cases of ACC had distinct missense mutations in KIT at both the genomic DNA and messenger RNA levels. These mutations caused G664R and R796G amino acid substitutions in the kinase domains. Surprisingly, the mutations were functionally inactive in cultured cells. We observed a significant reduction of MAPK (ERK1/2) activity in tumor cells, as assessed by immunohistochemistry. We performed further mutational analysis of the downstream effectors in the c-Kit pathway in the genes HRAS, KRAS, NRAS, BRAF, PIK3CA, and PTEN. This analysis revealed that two ACC tumors without KIT mutations had missense mutations in either KRAS or BRAF, causing S17N K-Ras and V590I B-Raf mutants, respectively. Our functional analysis showed that proteins with these mutations were also inactive in cultured cells. This is the first time that MAPK activity from the RTK signaling has been shown to be inhibited by gene mutations during tumor development. Because ACC seems to proliferate despite inactivation of the c-Kit signaling pathway, we suggest that selective inhibition of c-Kit is probably not a suitable treatment strategy for ACC.

UR - http://www.scopus.com/inward/record.url?scp=77956836493&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77956836493&partnerID=8YFLogxK

U2 - 10.1593/neo.10356

DO - 10.1593/neo.10356

M3 - Article

VL - 12

SP - 708

EP - 717

JO - Neoplasia

JF - Neoplasia

SN - 1522-8002

IS - 9

ER -