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The Unfolded Protein Response: A Novel Therapeutic Target for Poor Prognostic BRAF Mutant Colorectal Cancer

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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

Druh Článek v odborném periodiku
Časopis / Zdroj Molecular Cancer Therapeutics
Fakulta / Pracoviště MU

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Citace
www http://mct.aacrjournals.org/content/17/6/1280
Doi http://dx.doi.org/10.1158/1535-7163.MCT-17-0603
Klíčová slova ENDOPLASMIC-RETICULUM STRESS; SELECTIVE HDAC6 INHIBITOR; MULTIPLE-MYELOMA; ER STRESS; PROTEASOME INHIBITORS; AGGRESOME FORMATION; INDUCED APOPTOSIS; COLON-CANCER; CELL-DEATH; PATHWAY
Popis 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.