The unfolded protein response: a novel therapeutic target for poor prognostic BRAF mutant colorectal cancer

Sandra Van Schaeybroeck, Nicholas Forsythe, Alaa Refaat, Arman Javadi, Hajrah Khawaja, Jessica-Anne Weir, Heba Emam, Wendy Moore, Frank Burkamp, Vlad Popovici, Puthen Jithesh, Claudio Isella, Melissa LaBonte Wilson, Ian Mills, Patrick Johnston

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Abstract

Background
BRAFV600E mutations occur in ~10% of colorectal cancer (CRC), 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 CRC.

Method
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) CRC and an siRNA screen to characterize the biology underpinning the BRAFMT subgroup with poorest outcome.

Results
These analyses identified the unfolded protein response (UPR) as a novel and druggable pathway associated with the BRAFMT CRC subgroup with poorest outcome. We also found that oncogenic BRAF drives the endoplasmic reticulum (ER) stress 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 CRC 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.

Conclusion
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 CRC.
Original languageEnglish
Title of host publicationThe unfolded protein response: a novel therapeutic target for poor prognostic BRAF mutant colorectal cancer
PublisherNational Cancer Research Insitute
Publication statusPublished - 2017

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    Van Schaeybroeck, S., Forsythe, N., Refaat, A., Javadi, A., Khawaja, H., Weir, J-A., Emam, H., Moore, W., Burkamp, F., Popovici, V., Jithesh, P., Isella, C., LaBonte Wilson, M., Mills, I., & Johnston, P. (2017). The unfolded protein response: a novel therapeutic target for poor prognostic BRAF mutant colorectal cancer. In The unfolded protein response: a novel therapeutic target for poor prognostic BRAF mutant colorectal cancer National Cancer Research Insitute. http://abstracts.ncri.org.uk/abstract/the-unfolded-protein-response-a-novel-therapeutic-target-for-poor-prognostic-braf-mutant-colorectal-cancer/