Acetylsalicylic acid governs the effect of sorafenib in RAS- mutant cancers

Hammerlindl, Heinz, Ravindran Menon, Dinoop, Hammerlindl, Sabrina, Emran, Abdullah Al, Torrano, Joachim, Sproesser, Katrin, Thakkar, Divya, Xiao, Min, Atkinson, Victoria G., Gabrielli, Brian, Haass, Nikolas K., Herlyn, Meenhard, Krepler, Clemens and Schaider, Helmut (2018) Acetylsalicylic acid governs the effect of sorafenib in RAS- mutant cancers. Clinical Cancer Research, 24 5: 1090-1102. doi:10.1158/1078-0432.CCR-16-2118

Author Hammerlindl, Heinz
Ravindran Menon, Dinoop
Hammerlindl, Sabrina
Emran, Abdullah Al
Torrano, Joachim
Sproesser, Katrin
Thakkar, Divya
Xiao, Min
Atkinson, Victoria G.
Gabrielli, Brian
Haass, Nikolas K.
Herlyn, Meenhard
Krepler, Clemens
Schaider, Helmut
Title Acetylsalicylic acid governs the effect of sorafenib in RAS- mutant cancers
Journal name Clinical Cancer Research   Check publisher's open access policy
ISSN 1078-0432
Publication date 2018-03-01
Year available 2017
Sub-type Article (original research)
DOI 10.1158/1078-0432.CCR-16-2118
Open Access Status Not yet assessed
Volume 24
Issue 5
Start page 1090
End page 1102
Total pages 13
Place of publication Philadelphia, PA United States
Publisher American Association for Cancer Research
Language eng
Abstract Identify and characterize novel combinations of sorafenib with anti-inflammatory painkillers to target difficult to treat RAS-mutant cancer.

The cytotoxicity of acetylsalicylic acid (aspirin) in combination with the multikinase inhibitor sorafenib (Nexavar) was assessed in RAS-mutant cell lines in vitro. The underlying mechanism for the increased cytotoxicity was investigated using selective inhibitors and shRNA-mediated gene knockdown. In vitro results were confirmed in RAS-mutant xenograft mouse models in vivo.

The addition of aspirin but not isobutylphenylpropanoic acid (ibruprofen) or celecoxib (celebrex) significantly increased the in vitro cytotoxicity of sorafenib. Mechanistically, combined exposure resulted in increased BRAF/CRAF dimerization and the simultaneous hyper-activation of the AMPK and ERK pathways. Combining sorafenib with other AMPK activators, like metformin or A769662, was not sufficient to decrease cell viability due to sole activation of the AMPK pathway. The cytotoxicity of sorafenib and aspirin was blocked by inhibition of the AMPK or ERK pathways through shRNA or via pharmacological inhibitors of RAF (LY3009120), MEK (trametinib) or AMPK (compound C). The combination was found to be specific for RAS/RAF-mutant cells and had no significant effect in RAS/RAF-wild type keratinocytes or melanoma cells. In vivo treatment of human xenografts in NSG mice with sorafenib and aspirin significantly reduced tumor volume compared to each single-agent treatment alone.

Combined sorafenib and aspirin exerts cytotoxicity against RAS/RAF-mutant cells by simultaneously affecting two independent pathways and represents a promising novel strategy for the treatment of RAS-mutant cancers.
Keyword Nonsteroidal Antiinflammatory Drugs
Raf/mek/erk Pathway
Oncogenic Kras
Braf Inhibition
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID P01 CA114046
P50 CA174523
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Mater Research Institute-UQ (MRI-UQ)
HERDC Pre-Audit
UQ Diamantina Institute Publications
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Created: Wed, 10 Jan 2018, 13:56:47 EST