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Mutant Cancers 2 3 Heinz Hammerlindl1*, Dinoop Ravindran Menon1*, Sabrina Hammerlindl1, Abdullah Al

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Mutant Cancers 2 3 Heinz Hammerlindl1*, Dinoop Ravindran Menon1*, Sabrina Hammerlindl1, Abdullah Al Author Manuscript Published OnlineFirst on December 1, 2017; DOI: 10.1158/1078-0432.CCR-16-2118 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Hammerlindl et. al 1 Acetylsalicylic Acid Governs the Effect of Sorafenib in RAS Mutant Cancers 2 3 Heinz Hammerlindl1*, Dinoop Ravindran Menon1*, Sabrina Hammerlindl1, Abdullah Al 4 Emran1, Joachim Torrano1, Katrin Sproesser3, Divya Thakkar1, Min Xiao3, Victoria G. 5 Atkinson5, Brian Gabrielli4, Nikolas K. Haass2, Meenhard Herlyn3, Clemens Krepler3, Helmut 6 Schaider1,2† 7 8 1Dermatology Research Centre, The University of Queensland, The University of 9 Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia; 10 2The University of Queensland, The University of Queensland Diamantina Institute, 11 Translational Research Institute, Brisbane, Australia; 12 3The Wistar Institute, Philadelphia, PA, U.S.A.; 13 4Mater Medical Research Institute, The University of Queensland, Translational Research 14 Institute, Brisbane, Australia; 15 5Division of Cancer Services, Princess Alexandra Hospital, Brisbane, Australia; 16 *These authors contributed equally to the study 17 18 Running title: 19 Combined aspirin and sorafenib for RAS-mutant cancer therapy 20 21 Key words: 22 Melanoma, Lung Cancer, NRAS, Sorafenib, Aspirin, RAS, ERK, AMPK 23 24 25 26 27 28 1 Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 1, 2017; DOI: 10.1158/1078-0432.CCR-16-2118 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Hammerlindl et. al 1 2 Grant Support 3 This work was funded by the Epiderm Foundation (H.S.), the Princess Alexandra Hospital 4 Research Foundation (PARSS2016_NearMiss) (H.S.), NIH grants PO1 CA114046, P50 5 CA174523, and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (both 6 M.H.). A.A.E. is funded by The University of Queensland International Scholarship (UQI); 7 H.H. is funded by the International Postgraduate Research Scholarship (IPRS) and UQ 8 Centennial Scholarship (UQCent). N.K.H. is funded by the National Health and Medical 9 Research Council (APP1084893). 10 11 †Corresponding author 12 Helmut Schaider, MD, FACD 13 The University of Queensland Diamantina Institute 14 Translational Research Institute 15 The University of Queensland 16 37 Kent Street 17 Woolloongabba QLD 4102 18 Australia 19 T 61 7 3443 7395 20 F 61 7 3443 7799 21 E-mail: [email protected] 22 23 24 Conflict of interest 25 The authors declare no conflict of interest 26 27 2 Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 1, 2017; DOI: 10.1158/1078-0432.CCR-16-2118 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Hammerlindl et. al 1 Abstract 2 Purpose: Identify and characterize novel combinations of sorafenib with anti-inflammatory 3 painkillers to target difficult to treat RAS-mutant cancer. 4 Experimental Design: The cytotoxicity of acetylsalicylic acid (aspirin) in combination with 5 the multikinase inhibitor sorafenib (Nexavar®) was assessed in RAS-mutant cell lines in vitro. 6 The underlying mechanism for the increased cytotoxicity was investigated using selective 7 inhibitors and shRNA-mediated gene knockdown. In vitro results were confirmed in RAS- 8 mutant xenograft mouse models in vivo. 9 Results: The addition of aspirin but not isobutylphenylpropanoic acid (ibruprofen®) or 10 celecoxib (celebrex®) significantly increased the in vitro cytotoxicity of sorafenib. 11 Mechanistically, combined exposure resulted in increased BRAF/CRAF dimerization and the 12 simultaneous hyper-activation of the AMPK and ERK pathways. Combining sorafenib with 13 other AMPK activators, like metformin or A769662, was not sufficient to decrease cell 14 viability due to sole activation of the AMPK pathway. The cytotoxicity of sorafenib and aspirin 15 was blocked by inhibition of the AMPK or ERK pathways through shRNA or via 16 pharmacological inhibitors of RAF (LY3009120), MEK (trametinib) or AMPK (compound C). 17 The combination was found to be specific for RAS/RAF-mutant cells and had no significant 18 effect in RAS/RAF-wild type keratinocytes or melanoma cells. In vivo treatment of human 19 xenografts in NSG mice with sorafenib and aspirin significantly reduced tumor volume 20 compared to each single-agent treatment alone. 21 Conclusion: Combined sorafenib and aspirin exerts cytotoxicity against RAS/RAF-mutant 22 cells by simultaneously affecting two independent pathways and represents a promising 23 novel strategy for the treatment of RAS-mutant cancers. 24 25 26 27 28 3 Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 1, 2017; DOI: 10.1158/1078-0432.CCR-16-2118 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Hammerlindl et. al 1 Translational Relevance 2 To date, no therapies directly targeting mutant RAS have been approved, leaving 3 chemotherapy with very low response rates or immunotherapy as the only treatment options 4 for RAS-mutant cancers. Here we report a novel strategy to target RAS-mutant cancer, 5 especially NRAS-mutant melanoma, by combining the multi-kinase inhibitor sorafenib and 6 the non-steroidal anti-inflammatory drug acetylsalicylic acid (aspirin), both of which are 7 clinically approved and tested. The addition of aspirin strongly enhanced the in vitro and in 8 vivo cytotoxicity of otherwise ineffective sorafenib dosages. The combination of sorafenib 9 and aspirin but no other AMPK activators simultaneously induced activation of the AMPK and 10 ERK pathways, which are both necessary for drug effectivity. This finding suggests that 11 combining sorafenib with aspirin could be a viable treatment strategy for RAS-mutant 12 cancers including NRAS-mutant melanoma. 13 4 Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 1, 2017; DOI: 10.1158/1078-0432.CCR-16-2118 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Hammerlindl et. al 1 Introduction 2 Mutant neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS) was the first oncogene 3 identified in melanoma (1) and it is now known that approximately 20% of all melanomas 4 harbor mutations in NRAS, 2% in KRAS and 1% in HRAS (2). While KRAS and HRAS only 5 play a minor role for melanoma, KRAS in particular is frequently mutated in other cancers, 6 including lung, colon and pancreatic carcinomas (3). Mechanistically, RAS proteins are 7 GTPases that activate downstream signaling pathways involved in proliferation and cell 8 survival upon GTP binding (3). Genetic mutations are located in codons 12, 13 and 61, and 9 more than 80% of mutant NRAS harbor a mutation at codon 61 (4). Mutations result in 10 reduced GTPase activity, which causes preferential binding of GTP and therefore constitutive 11 activation of RAS signaling (5). In recent years the advent of targeted therapies has 12 advanced melanoma treatment but focused on mutant BRAF, whereas no strategies directly 13 targeting mutant NRAS have been approved (6,7). Inhibitors for RAS are particularly difficult 14 to develop (8,9) leaving low response chemotherapy (10) or immunotherapy (11) with high 15 toxicity rates as therapeutic strategies for patients with NRAS-mutant melanoma. Attempts to 16 directly target RAS mutations include farnesyl transferase inhibitors, which are supposed to 17 prevent posttranslational modifications required for the integration of RAS into the plasma 18 membrane (12) thus preventing the interaction of RAS and the prenyl-binding protein PDEδ 19 (13). Unfortunately, farnesyl transferase inhibitors showed disappointing results in clinical 20 settings (12) and inhibitors of PDEδ binding to farnesylated KRAS still require more 21 development to optimize the drugs (14). Other attempts to target RAS-mutant cancers 22 include blocking RAS downstream targets. Inhibition of MEK (6,15) or MEK in combination 23 with PI3K/mTOR inhibitors have shown promising results (10). However, inhibition of MEK 24 leads to the development of resistance, similar to strategies in BRAF-mutant melanoma (16). 25 Several mechanisms of resistance have been proposed for NRAS-mutant melanoma 26 including PDGF receptor β signaling (17) emphasizing the importance of novel single or 27 combination therapies for sustained treatment. Sorafenib (Nexavar, BAY 43–9006; Bayer 28 Healthcare Pharmaceuticals) is a multikinase inhibitor that targets both C-RAF and B-RAF as 5 Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 1, 2017; DOI: 10.1158/1078-0432.CCR-16-2118 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Hammerlindl et. al 1 well as the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and 2 platelet-derived growth factor receptor family (PDGFR-) (18), among others. Sorafenib is 3 FDA-approved for the treatment of advanced renal cell carcinoma and patients
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