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| 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
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| 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.
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| Overall design |
SNP arrays were profiled in PU-H71-sensitive and resistant A549, MDA-MB-231 and SW480 cell lines.
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| 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 |
| E-mail(s) |
lars.bullinger@charite.de
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| Phone |
+49-30-450-553111
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| Organization name |
Charité
|
| Department |
Hematology, Oncology and Tumorimmunology
|
| Street address |
Augustenburger Platz 1
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| City |
Berlin |
| ZIP/Postal code |
13353 |
| Country |
Germany |
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| Platforms (1) |
| GPL6801 |
[GenomeWideSNP_6] Affymetrix Genome-Wide Human SNP 6.0 Array |
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| Samples (6)
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| This SubSeries is part of SuperSeries: |
| GSE85734 |
Prospective identification of resistance mechanisms to HSP90 inhibition in KRAS mutant cancer cells |
|
| Relations |
| BioProject |
PRJNA339221 |
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