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Series GSE85733 Query DataSets for GSE85733
Status Public on Dec 31, 2016
Title Prospective identification of resistance mechanisms to HSP90 inhibition in KRAS mutant cancer cells [GenomeWideSNP_6]
Organism Homo sapiens
Experiment type SNP genotyping by SNP array
Summary Inhibition of the HSP90 chaperone results in depletion of many signaling proteins that drive tumorigenesis, such as downstream effectors of KRAS, the most commonly mutated human oncogene. As a consequence, several small-molecule HSP90 inhibitors are being evaluated in clinical trials as anticancer agents. To prospectively identify mechanisms through which HSP90-dependent cancer cells evade pharmacologic HSP90 blockade, we generated multiple mutant KRAS-driven cancer cell lines with acquired resistance to the purine-scaffold HSP90 inhibitor PU-H71. All cell lines retained dependence on HSP90 function, as evidenced by sensitivity to short hairpin RNA-mediated suppression of HSP90AA1 or HSP90AB1 (also called HSP90α and HSP90β, respectively), and exhibited two types of genomic alterations that interfere with the effects of PU-H71 on cell viability and proliferation: (i) a Y142N missense mutation in the ATP-binding domain of HSP90α that co-occurred with amplification of the HSP90AA1 locus, (ii) genomic amplification and overexpression of the ABCB1 gene encoding the MDR1 drug efflux pump. In support of a functional role for these alterations, exogenous expression of HSP90α Y142N conferred PU-H71 resistance to HSP90-dependent cells, and pharmacologic MDR1 inhibition with tariquidar or lowering ABCB1 expression restored sensitivity to PU-H71 in ABCB1-amplified cells. Finally, comparison with structurally distinct HSP90 inhibitors currently in clinical development revealed that PU-H71 resistance could be overcome, in part, by ganetespib (also known as STA9090) but not tanespimycin (also known as 17-AAG). Together, these data identify potential mechanisms of acquired resistance to small molecules targeting HSP90 that may warrant proactive screening for additional HSP90 inhibitors or rational combination therapies.
Overall design SNP arrays were profiled in PU-H71-sensitive and resistant A549, MDA-MB-231 and SW480 cell lines.
Contributor(s) Bullinger L, Rouhi A, Fröhling S, Scholl C
Citation(s) 28032595
Submission date Aug 17, 2016
Last update date Nov 27, 2018
Contact name Lars Bullinger
Phone +49-30-450-553111
Organization name Charité
Department Hematology, Oncology and Tumorimmunology
Street address Augustenburger Platz 1
City Berlin
ZIP/Postal code 13353
Country Germany
Platforms (1)
GPL6801 [GenomeWideSNP_6] Affymetrix Genome-Wide Human SNP 6.0 Array
Samples (6)
GSM2283321 CB_A549-P
GSM2283322 CB_A549-R
GSM2283323 CB_MDA-P
This SubSeries is part of SuperSeries:
GSE85734 Prospective identification of resistance mechanisms to HSP90 inhibition in KRAS mutant cancer cells
BioProject PRJNA339221

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE85733_RAW.tar 257.7 Mb (http)(custom) TAR (of CEL, CHP)
Processed data included within Sample table
Processed data provided as supplementary file

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