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The Unfolded Protein Response: A Novel Therapeutic Target for Poor Prognostic BRAF Mutant Colorectal Cancer
N. Forsythe, A. Refaat, A. Javadi, H. Khawaja, JA. Weir, H. Emam, WL. Allen, F. Burkamp, V. Popovici, PV. Jithesh, C. Isella, MJ. Labonte, IG. Mills, PG. Johnston, S. Van Schaeybroeck,
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články, práce podpořená grantem
Grantová podpora
C212/A13721
Cancer Research UK - United Kingdom
C13749/A13172
Cancer Research UK - United Kingdom
Open Access Digital Library od 2001-11-01
Open Access Digital Library od 2001-11-01
Odkazy
PubMed
29483217
DOI
10.1158/1535-7163.mct-17-0603
Knihovny.cz E-zdroje
- MeSH
- antitumorózní látky farmakologie MeSH
- apoptóza účinky léků genetika MeSH
- biologické modely MeSH
- inhibitory proteinkinas farmakologie MeSH
- kolorektální nádory farmakoterapie genetika metabolismus mortalita MeSH
- kyseliny hydroxamové farmakologie MeSH
- lidé MeSH
- MAP kinasový signální systém MeSH
- mutace * MeSH
- nádorové biomarkery MeSH
- nádorové buněčné linie MeSH
- oligopeptidy farmakologie MeSH
- prognóza MeSH
- proteiny tepelného šoku genetika metabolismus MeSH
- proteosyntéza MeSH
- protoonkogenní proteiny B-raf antagonisté a inhibitory genetika metabolismus MeSH
- pyrimidiny farmakologie MeSH
- signální dráha UPR účinky léků MeSH
- signální transdukce účinky léků MeSH
- stres endoplazmatického retikula účinky léků genetika MeSH
- transkripční faktor CHOP genetika metabolismus MeSH
- viabilita buněk účinky léků genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BRAFV600E mutations occur in ∼10% of colorectal cancer cases, are associated with poor survival, and have limited responses to BRAF/MEK inhibition with or without EGFR inhibition. There is an unmet need to understand the biology of poor prognostic BRAFMT colorectal cancer. We have used differential gene expression and pathway analyses of untreated stage II and stage III BRAFMT (discovery set: n = 31; validation set: n = 26) colorectal cancer, and an siRNA screen to characterize the biology underpinning the BRAFMT subgroup with poorest outcome. These analyses identified the unfolded protein response (UPR) as a novel and druggable pathway associated with the BRAFMT colorectal cancer subgroup with poorest outcome. We also found that oncogenic BRAF drives endoplasmic reticulum (ER) stress and UPR pathway activation through MEK/ERK. Furthermore, inhibition of GRP78, the master regulator of the UPR, using siRNA or small molecule inhibition, resulted in acute ER stress and apoptosis, in particular in BRAFMT colorectal cancer cells. In addition, dual targeting of protein degradation using combined Carfilzomib (proteasome inhibitor) and ACY-1215 (HDAC6-selective inhibitor) treatment resulted in marked accumulation of protein aggregates, acute ER stress, apoptosis, and therapeutic efficacy in BRAFMT in vitro and xenograft models. Mechanistically, we found that the apoptosis following combined Carfilzomib/ACY-1215 treatment is mediated through increased CHOP expression. Taken together, our findings indicate that oncogenic BRAF induces chronic ER stress and that inducers of acute ER stress could be a novel treatment strategy for poor prognostic BRAFMT colorectal cancer. Mol Cancer Ther; 17(6); 1280-90. ©2018 AACR.
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- $a BRAFV600E mutations occur in ∼10% of colorectal cancer cases, are associated with poor survival, and have limited responses to BRAF/MEK inhibition with or without EGFR inhibition. There is an unmet need to understand the biology of poor prognostic BRAFMT colorectal cancer. We have used differential gene expression and pathway analyses of untreated stage II and stage III BRAFMT (discovery set: n = 31; validation set: n = 26) colorectal cancer, and an siRNA screen to characterize the biology underpinning the BRAFMT subgroup with poorest outcome. These analyses identified the unfolded protein response (UPR) as a novel and druggable pathway associated with the BRAFMT colorectal cancer subgroup with poorest outcome. We also found that oncogenic BRAF drives endoplasmic reticulum (ER) stress and UPR pathway activation through MEK/ERK. Furthermore, inhibition of GRP78, the master regulator of the UPR, using siRNA or small molecule inhibition, resulted in acute ER stress and apoptosis, in particular in BRAFMT colorectal cancer cells. In addition, dual targeting of protein degradation using combined Carfilzomib (proteasome inhibitor) and ACY-1215 (HDAC6-selective inhibitor) treatment resulted in marked accumulation of protein aggregates, acute ER stress, apoptosis, and therapeutic efficacy in BRAFMT in vitro and xenograft models. Mechanistically, we found that the apoptosis following combined Carfilzomib/ACY-1215 treatment is mediated through increased CHOP expression. Taken together, our findings indicate that oncogenic BRAF induces chronic ER stress and that inducers of acute ER stress could be a novel treatment strategy for poor prognostic BRAFMT colorectal cancer. Mol Cancer Ther; 17(6); 1280-90. ©2018 AACR.
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