Research Papers:

Prospective identification of resistance mechanisms to HSP90 inhibition in KRAS mutant cancer cells

Arefeh Rouhi, Christina Miller, Sarah Grasedieck, Stefanie Reinhart, Britta Stolze, Hartmut Döhner, Florian Kuchenbauer, Lars Bullinger, Stefan Fröhling and Claudia Scholl _

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Oncotarget. 2017; 8:7678-7690. https://doi.org/10.18632/oncotarget.13841

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Arefeh Rouhi1, Christina Miller1, Sarah Grasedieck1, Stefanie Reinhart2, Britta Stolze2, Hartmut Döhner1, Florian Kuchenbauer1, Lars Bullinger1, Stefan Fröhling2,3,4,*, Claudia Scholl2,4,*

1Department of Internal Medicine III, Ulm University, Ulm, Germany

2Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany

3Section for Personalized Oncology, Heidelberg University Hospital, Heidelberg, Germany

4German Cancer Consortium (DKTK), Heidelberg, Germany

*shared senior authorship of this article

Correspondence to:

Claudia Scholl, email: claudia.scholl@nct-heidelberg.de

Keywords: drug resistance, HSP90 inhibition, PU-H71, mutant KRAS, MDR1

Received: August 02, 2016     Accepted: November 30, 2016     Published: December 09, 2016


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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