Prospective identification of resistance mechanisms to HSP90 inhibition in KRAS mutant cancer cells
Abstract: 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 an...
Gespeichert in:
| Hauptverfasser: | , , , |
|---|---|
| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
2017
|
| In: |
OncoTarget
Year: 2017, Jahrgang: 8, Heft: 5, Pages: 7678-7690 |
| ISSN: | 1949-2553 |
| DOI: | 10.18632/oncotarget.13841 |
| Online-Zugang: | Verlag, kostenfrei, Volltext: http://dx.doi.org/10.18632/oncotarget.13841 Verlag, kostenfrei, Volltext: http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=13841&pubmed-linkout=1 
|
| Verfasserangaben: | Arefeh Rouhi, Christina Miller, Sarah Grasedieck, Stefanie Reinhart, Britta Stolze, Hartmut Döhner, Florian Kuchenbauer, Lars Bullinger, Stefan Fröhling, Claudia Scholl |
MARC
| LEADER | 00000caa a2200000 c 4500 | ||
|---|---|---|---|
| 001 | 1572485388 | ||
| 003 | DE-627 | ||
| 005 | 20251126085128.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 180430s2017 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.18632/oncotarget.13841 |2 doi | |
| 035 | |a (DE-627)1572485388 | ||
| 035 | |a (DE-576)502485388 | ||
| 035 | |a (DE-599)BSZ502485388 | ||
| 035 | |a (OCoLC)1341007975 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rda | ||
| 041 | |a eng | ||
| 084 | |a 33 |2 sdnb | ||
| 100 | 1 | |a Rouhi, Arefeh |e VerfasserIn |0 (DE-588)115688117X |0 (DE-627)1019843179 |0 (DE-576)502485299 |4 aut | |
| 245 | 1 | 0 | |a Prospective identification of resistance mechanisms to HSP90 inhibition in KRAS mutant cancer cells |c Arefeh Rouhi, Christina Miller, Sarah Grasedieck, Stefanie Reinhart, Britta Stolze, Hartmut Döhner, Florian Kuchenbauer, Lars Bullinger, Stefan Fröhling, Claudia Scholl |
| 264 | 1 | |c 2017 | |
| 300 | |a 13 | ||
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Published online: December 09, 2016 | ||
| 500 | |a Gesehen am 30.04.2018 | ||
| 520 | |a Abstract: 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 | ||
| 700 | 1 | |a Reinhart, Stefanie |e VerfasserIn |0 (DE-588)1137033533 |0 (DE-627)893982334 |0 (DE-576)491067046 |4 aut | |
| 700 | 1 | |a Fröhling, Stefan |d 1969- |e VerfasserIn |0 (DE-588)120890046 |0 (DE-627)080950302 |0 (DE-576)188733930 |4 aut | |
| 700 | 1 | |a Scholl, Claudia |d 1971- |e VerfasserIn |0 (DE-588)128803533 |0 (DE-627)380643197 |0 (DE-576)187440271 |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t OncoTarget |d [Erscheinungsort nicht ermittelbar] : Impact Journals LLC, 2010 |g 8(2017), 5, Seite 7678-7690 |h Online-Ressource |w (DE-627)63035975X |w (DE-600)2560162-3 |w (DE-576)325343764 |x 1949-2553 |7 nnas |a Prospective identification of resistance mechanisms to HSP90 inhibition in KRAS mutant cancer cells |
| 773 | 1 | 8 | |g volume:8 |g year:2017 |g number:5 |g pages:7678-7690 |g extent:13 |a Prospective identification of resistance mechanisms to HSP90 inhibition in KRAS mutant cancer cells |
| 856 | 4 | 0 | |u http://dx.doi.org/10.18632/oncotarget.13841 |x Verlag |x Resolving-System |z kostenfrei |3 Volltext |
| 856 | 4 | 0 | |u http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=13841&pubmed-linkout=1 |x Verlag |z kostenfrei |3 Volltext |
| 951 | |a AR | ||
| 992 | |a 20180430 | ||
| 993 | |a Article | ||
| 994 | |a 2017 | ||
| 998 | |g 128803533 |a Scholl, Claudia |m 128803533:Scholl, Claudia |d 50000 |e 50000PS128803533 |k 0/50000/ |p 10 |y j | ||
| 998 | |g 120890046 |a Fröhling, Stefan |m 120890046:Fröhling, Stefan |d 50000 |e 50000PF120890046 |k 0/50000/ |p 9 | ||
| 998 | |g 1137033533 |a Reinhart, Stefanie |m 1137033533:Reinhart, Stefanie |d 50000 |e 50000PR1137033533 |k 0/50000/ |p 4 | ||
| 999 | |a KXP-PPN1572485388 |e 300762116X | ||
| BIB | |a Y | ||
| SER | |a journal | ||
| JSO | |a {"name":{"displayForm":["Arefeh Rouhi, Christina Miller, Sarah Grasedieck, Stefanie Reinhart, Britta Stolze, Hartmut Döhner, Florian Kuchenbauer, Lars Bullinger, Stefan Fröhling, Claudia Scholl"]},"language":["eng"],"person":[{"role":"aut","family":"Rouhi","given":"Arefeh","display":"Rouhi, Arefeh"},{"given":"Stefanie","display":"Reinhart, Stefanie","family":"Reinhart","role":"aut"},{"role":"aut","family":"Fröhling","display":"Fröhling, Stefan","given":"Stefan"},{"display":"Scholl, Claudia","given":"Claudia","family":"Scholl","role":"aut"}],"recId":"1572485388","note":[" Published online: December 09, 2016","Gesehen am 30.04.2018"],"title":[{"title_sort":"Prospective identification of resistance mechanisms to HSP90 inhibition in KRAS mutant cancer cells","title":"Prospective identification of resistance mechanisms to HSP90 inhibition in KRAS mutant cancer cells"}],"type":{"media":"Online-Ressource","bibl":"article-journal"},"id":{"doi":["10.18632/oncotarget.13841"],"eki":["1572485388"]},"physDesc":[{"extent":"13 S."}],"relHost":[{"recId":"63035975X","title":[{"subtitle":"open access impact journal","title":"OncoTarget","title_sort":"OncoTarget"}],"physDesc":[{"extent":"Online-Ressource"}],"id":{"issn":["1949-2553"],"eki":["63035975X"],"zdb":["2560162-3"]},"origin":[{"dateIssuedKey":"2010","publisherPlace":"[Erscheinungsort nicht ermittelbar]","publisher":"Impact Journals LLC","dateIssuedDisp":"2010-"}],"language":["eng"],"part":{"volume":"8","year":"2017","extent":"13","pages":"7678-7690","issue":"5","text":"8(2017), 5, Seite 7678-7690"},"note":["Gesehen am 16.08.2018"],"pubHistory":["1.2010,Mai -"],"disp":"Prospective identification of resistance mechanisms to HSP90 inhibition in KRAS mutant cancer cellsOncoTarget","type":{"media":"Online-Ressource","bibl":"periodical"}}],"origin":[{"dateIssuedKey":"2017","dateIssuedDisp":"2017"}]} | ||
| SRT | |a ROUHIAREFEPROSPECTIV2017 | ||