Next Article in Journal
De Novo RNA Sequencing and Expression Analysis of Aconitum carmichaelii to Analyze Key Genes Involved in the Biosynthesis of Diterpene Alkaloids
Previous Article in Journal
Composition and Bioactivity of Essential Oil from Citrus grandis (L.) Osbeck ‘Mato Peiyu’ Leaf
Previous Article in Special Issue
New and Old Genes Associated with Primary and Established Responses to Cisplatin and Topotecan Treatment in Ovarian Cancer Cell Lines
Article Menu

Export Article

Open AccessArticle
Molecules 2017, 22(12), 2152; doi:10.3390/molecules22122152

A Novel Receptor Tyrosine Kinase Switch Promotes Gastrointestinal Stromal Tumor Drug Resistance

1
Department of Pathology, Kazan State Medical University, Kazan 420012, Russia
2
Kazan Federal (Volga Region) State University, Kazan 420008, Russia
3
Innovation Center, RIKEN, Yokohama 230-0045, Japan
4
Preventive Medicine and Diagnosis Innovation Program, RIKEN, Yokohama 230-0045, Japan
*
Author to whom correspondence should be addressed.
Received: 21 September 2017 / Revised: 27 November 2017 / Accepted: 1 December 2017 / Published: 5 December 2017
(This article belongs to the Special Issue Counteracting Drug Resistant Mechanisms in Cancer)
View Full-Text   |   Download PDF [6977 KB, uploaded 12 December 2017]   |  

Abstract

The fact that most gastrointestinal stromal tumors (GISTs) acquire resistance to imatinib (IM)-based targeted therapy remains the main driving force to identify novel molecular targets that are capable to increase GISTs sensitivity to the current therapeutic regimens. Secondary resistance to IM in GISTs typically occurs due to several mechanisms that include hemi- or homo-zygous deletion of the wild-type KIT allele, overexpression of focal adhesion kinase (FAK) and insulin-like growth factor receptor I (IGF-1R) amplification, BRAF mutation, a RTK switch (loss of c-KIT and gain of c-MET/AXL), etc. We established and characterized the IM-resistant GIST T-1 cell line (GIST T-1R) lacking secondary c-KIT mutations typical for the IM-resistant phenotype. The resistance to IM in GIST T-1R cells was due to RTK switch (loss of c-KIT/gain of FGFR2α). Indeed, we have found that FGFR inhibition reduced cellular viability, induced apoptosis and affected the growth kinetics of the IM-resistant GISTs in vitro. In contrast, IM-naive GIST T-1 parental cells were not susceptible to FGFR inhibition. Importantly, inhibition of FGF-signaling restored the susceptibility to IM in IM-resistant GISTs. Additionally, IM-resistant GISTs were less susceptible to certain chemotherapeutic agents as compared to parental IM-sensitive GIST cells. The chemoresistance in GIST T-1R cells is not due to overexpression of ABC-related transporter proteins and might be the result of upregulation of DNA damage signaling and repair (DDR) genes involved in DNA double-strand break (DSB) repair pathways (e.g., XRCC3, Rad51, etc.). Taken together, the established GIST T-1R cell subline might be used for in vitro and in vivo studies to examine the efficacy and prospective use of FGFR inhibitors for patients with IM-resistant, un-resectable and metastatic forms of GISTs with the type of RTK switch indicated above. View Full-Text
Keywords: gastrointestinal stromal tumor cells (GISTs); imatinib (IM); FGFR2α; resistance; receptor tyrosine kinase (RTK) inhibitors; chemotherapeutic drugs gastrointestinal stromal tumor cells (GISTs); imatinib (IM); FGFR2α; resistance; receptor tyrosine kinase (RTK) inhibitors; chemotherapeutic drugs
Figures

Figure 1

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

Scifeed alert for new publications

Never miss any articles matching your research from any publisher
  • Get alerts for new papers matching your research
  • Find out the new papers from selected authors
  • Updated daily for 49'000+ journals and 6000+ publishers
  • Define your Scifeed now

SciFeed Share & Cite This Article

MDPI and ACS Style

Boichuk, S.; Galembikova, A.; Dunaev, P.; Valeeva, E.; Shagimardanova, E.; Gusev, O.; Khaiboullina, S. A Novel Receptor Tyrosine Kinase Switch Promotes Gastrointestinal Stromal Tumor Drug Resistance. Molecules 2017, 22, 2152.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]

Molecules EISSN 1420-3049 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top