17-AAG inhibits vemurafenib-associated MAP kinase activation and is synergistic with cellular immunotherapy in a murine melanoma model.

PloS One
Sandeep S JoshiThomas J Hornyak

Abstract

Heat shock protein 90 (HSP90) is a molecular chaperone which stabilizes client proteins with important roles in tumor growth. 17-allylamino-17-demethoxygeldanamycin (17-AAG), an inhibitor of HSP90 ATPase activity, occupies the ATP binding site of HSP90 causing a conformational change which destabilizes client proteins and directs them towards proteosomal degradation. Malignant melanomas have active RAF-MEK-ERK signaling which can occur either through an activating mutation in BRAF (BRAFV600E) or through activation of signal transduction upstream of BRAF. Prior work showed that 17-AAG inhibits cell growth in BRAFV600E and BRAF wildtype (BRAFWT) melanomas, although there were conflicting reports about the dependence of BRAFV600E and BRAFWT upon HSP90 activity for stability. Here, we demonstrate that BRAFWT and CRAF are bound by HSP90 in BRAFWT, NRAS mutant melanoma cells. HSP90 inhibition by 17-AAG inhibits ERK signaling and cell growth by destabilizing CRAF but not BRAFWT in the majority of NRAS mutant melanoma cells. The highly-selective BRAFV600E inhibitor, PLX4032 (vemurafenib), inhibits ERK signaling and cell growth in mutant BRAF melanoma cells, but paradoxically enhances signaling in cells with wild-type BRAF. In our study...Continue Reading

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Citations

Oct 30, 2019·Apoptosis : an International Journal on Programmed Cell Death·Aleksandra Mielczarek-LewandowskaMalgorzata Czyz
Dec 15, 2019·Cellular Signalling·Khadeja-Tul KubraNektarios Barabutis
Jun 25, 2021·Science Advances·Erik B SchiferleShadmehr Demehri
Mar 5, 2021·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Shang LiXiao Zhu

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Methods Mentioned

BETA
Co-immunoprecipitation
electrophoresis
Immunoprecipitation
flow cytometry
xenografting
xenograft
protein assay
ELISA
transfection
transgenic

Software Mentioned

FlowJo
Graphpad Prism

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