The unfolded protein response: A novel therapeutic target for poor prognostic braf mutant colorectal cancer

Nicholas Forsythe, 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, Sandra Van Schaeybroeck

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

BRAF V600E 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 ¼ 31; validation set: n ¼ 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.

Original languageEnglish
Pages (from-to)1280-1290
Number of pages11
JournalMolecular Cancer Therapeutics
Volume17
Issue number6
DOIs
Publication statusPublished - Jun 2018

    Fingerprint

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Forsythe, N., Refaat, A., Javadi, A., Khawaja, H., Weir, J. A., Emam, H., Allen, W. L., Burkamp, F., Popovici, V., Jithesh, P. V., Isella, C., Labonte, M. J., Mills, I. G., Johnston, P. G., & Van Schaeybroeck, S. (2018). The unfolded protein response: A novel therapeutic target for poor prognostic braf mutant colorectal cancer. Molecular Cancer Therapeutics, 17(6), 1280-1290. https://doi.org/10.1158/1535-7163.MCT-17-0603