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Molecular Biology

, Volume 52, Issue 3, pp 398–405 | Cite as

Inactivation of Receptor Tyrosine Kinases Overcomes Resistance to Targeted B-RAF Inhibitors in Melanoma Cell Lines

  • O. O. Ryabaya
  • A. A. Malysheva
  • Yu. A. Khochenkova
  • E. Sh. Solomko
  • D. A. Khochenkov
Molecular Cell Biology
  • 29 Downloads

Abstract

The discovery of B-RAF activating mutations in malignant melanoma cells has led to the development of a number of targeted drugs, which block exclusively the mutant B-RAF protein. Tumor cells often acquire resistance to B-RAF inhibitors via activation of alternative signaling pathways. One of the resistance mechanisms is activation of PDGF, VEGF, c-KIT, and certain other tyrosine kinases. The possibility of overcoming the resistance to the B-RAF inhibitor Vemurafenib by inactivating receptor tyrosine kinases (RTKs) was studied in metastatic melanoma cell lines differing in B-RAF mutations and RTK activity. It was found that RTK inactivation may help to overcome resistance to B-RAF inhibitors via inhibition of tyrosine kinase phosphorylation and a subsequent blocking of the PI3K-AKT-mTOR and MEK-ERK1/2 downstream signaling pathways. The changes eventually mitigated the cell growth and enhanced the Vemurafenibdependent cell cycle arrest.

Keywords

melanoma resistance tyrosine kinases Vemurafenib 

Abbreviations

DMSO

dimethyl sulfoxide

MM

metastatic melanoma

MTT

3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide

RTK

receptor tyrosine kinase

TGI

tumor growth inhibition

FBS

fetal bovine serum

EDTA

ethylenediaminetetraacetic acid

AKT

RAC-α-serine/threonineprotein kinase

B-RAF

B-Raf proto-оncogene, serine/threonine kinase

CD31

cluster of differentiation 31 (platelet endothelial cell adhesion molecule)

ErbB/HER

epidermal growth factor receptor

ERK1/2

extracellular signal-regulated kinase 1/2

c-KIT

thyrosine protein kinase KIT (mast/stem cell growth factor receptor)

MEK

mitogen-activated protein kinase kinase

c-MET

tyrosine-protein kinase Met (hepatocyte growth factor)

PDGF

platelet-derived growth factor

PDGFRα and PDGFRβ

platelet-derived growth factor receptors α and β

PI3K

phosphoinositide 3-kinase

mTOR

mammalian target of rapamycin

VEGF

vascular endothelial growth factor

VEGFR2

vascular endothelial growth factor receptor 2

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Copyright information

© Pleiades Publishing, Inc. 2018

Authors and Affiliations

  • O. O. Ryabaya
    • 1
    • 2
  • A. A. Malysheva
    • 1
  • Yu. A. Khochenkova
    • 1
  • E. Sh. Solomko
    • 1
  • D. A. Khochenkov
    • 1
  1. 1.Blokhin Cancer Research CenterMinistry of Health of the Russian FederationMoscowRussia
  2. 2.Pirogov Russian National Research Medical UniversityMinistry of Health of the Russian FederationMoscowRussia

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