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@article{1487426,
author = {Forsythe, Nicholas and Refaat, Alaa and Javadi, Arman and Khawaja, Hajrah and Weir, JessicaandAnne and Emam, Heba and Allen, Wendy L. and Burkamp, Frank and Popovici, Vlad and Jithesh, Puthen V. and Isella, Claudio and Labonte, Melissa J. and Mills, Ian G. and Johnston, Patrick G. and Van Schaeybroeck, Sandra},
article_location = {PHILADELPHIA},
article_number = {6},
doi = {http://dx.doi.org/10.1158/1535-7163.MCT-17-0603},
keywords = {ENDOPLASMIC-RETICULUM STRESS; SELECTIVE HDAC6 INHIBITOR; MULTIPLE-MYELOMA; ER STRESS; PROTEASOME INHIBITORS; AGGRESOME FORMATION; INDUCED APOPTOSIS; COLON-CANCER; CELL-DEATH; PATHWAY},
language = {eng},
issn = {1535-7163},
journal = {Molecular Cancer Therapeutics},
title = {The Unfolded Protein Response: A Novel Therapeutic Target for Poor Prognostic BRAF Mutant Colorectal Cancer},
url = {http://mct.aacrjournals.org/content/17/6/1280},
volume = {17},
year = {2018}
}
TY - JOUR
ID - 1487426
AU - Forsythe, Nicholas - Refaat, Alaa - Javadi, Arman - Khawaja, Hajrah - Weir, Jessica-Anne - Emam, Heba - Allen, Wendy L. - Burkamp, Frank - Popovici, Vlad - Jithesh, Puthen V. - Isella, Claudio - Labonte, Melissa J. - Mills, Ian G. - Johnston, Patrick G. - Van Schaeybroeck, Sandra
PY - 2018
TI - The Unfolded Protein Response: A Novel Therapeutic Target for Poor Prognostic BRAF Mutant Colorectal Cancer
JF - Molecular Cancer Therapeutics
VL - 17
IS - 6
SP - 1280-1290
EP - 1280-1290
PB - American Association for Cancer Research
SN - 15357163
KW - ENDOPLASMIC-RETICULUM STRESS
KW - SELECTIVE HDAC6 INHIBITOR
KW - MULTIPLE-MYELOMA
KW - ER STRESS
KW - PROTEASOME INHIBITORS
KW - AGGRESOME FORMATION
KW - INDUCED APOPTOSIS
KW - COLON-CANCER
KW - CELL-DEATH
KW - PATHWAY
UR - http://mct.aacrjournals.org/content/17/6/1280
L2 - http://mct.aacrjournals.org/content/17/6/1280
N2 - BRAF(V600E) mutations occur in similar to 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 increasedCHOPexpression. 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.
ER -
FORSYTHE, Nicholas, Alaa REFAAT, Arman JAVADI, Hajrah KHAWAJA, Jessica-Anne WEIR, Heba EMAM, Wendy L. ALLEN, Frank BURKAMP, Vlad POPOVICI, Puthen V. JITHESH, Claudio ISELLA, Melissa J. LABONTE, Ian G. MILLS, Patrick G. JOHNSTON and Sandra VAN SCHAEYBROECK. The Unfolded Protein Response: A Novel Therapeutic Target for Poor Prognostic BRAF Mutant Colorectal Cancer. \textit{Molecular Cancer Therapeutics}. PHILADELPHIA: American Association for Cancer Research, 2018, vol.~17, No~6, p.~1280-1290. ISSN~1535-7163. Available from: https://dx.doi.org/10.1158/1535-7163.MCT-17-0603.
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