24PTherapeutic implications of MTH1 inhibitor TH1579 in cutaneous malignant melanoma. (7th November 2019)

• Record Type: Journal Article
• Authors: Das, I; Gad, H; Bräutigam, L; Pudelko, L; Tuominen, R; Höiom, V; Almlöf, I; Hansson, J; Helleday, T; Brage, S E; Berglund, U W
• Is Part Of: Annals of oncology. Volume 30(2019)Supplement 7
• Publication Date: 2019-11-07
• Subjects: Oncology -- Periodicals; 616.992
• DOI: 10.1093/annonc/mdz413.029
• Languages: English
• ISSNs: 0923-7534

Abstract

Abstract: Background: Cutaneous malignant melanoma (CMM) is the main cause of skin cancer related deaths with approximately 230, 000 new cases diagnosed worldwide annually. Advanced disease has poor prognosis due to unsuccessful treatment. BRAF inhibitors have shown promising clinical results with longer progression free survival but relapses are common and overall survival (OS) rates have been modest. Currently, there is a paucity of targeted treatment options for patients harboring NRAS mutation who have a worse OS compared to patients with wildtype NRAS. The DNA repair protein MTH1 sanitizes the dNTP pool by hydrolyzing harmful 8-oxodG which can be induced by reactive oxygen species (ROS). MTH1 is upregulated in several cancers including CMM. CMM has high levels of ROS and thus inhibition of MTH1 and other DNA repair proteins may be a plausible therapeutic strategy. Methods: Here we used a panel of CMM cells, patient derived cells and an orthotopic zebrafish disease model to measure cell viability after treatment with MTH1 inhibitor TH1579 using real time imaging and luminescence. We performed AmpliSEQ analysis (patient tumor material), FACS, time lapse microscopy, immunofluorescence and western blot to do functional and molecular studies. Results: We observed loss in cell viability and reduction in sphere growth upon treatment with TH1579 both in vitro and in vivo. FACS analysis confirmed induction of cell death in BRAF and NRAS mutant cell lines but not in the wild type cells, which showed induction of cell cycle arrest. Heterogeneous co-cultures of CMM cells were sensitive to TH1579, thus suggesting its broad clinical applicability. The BRAF mutant cells were further sensitized by co-treatment of TH1579 with BRAF inhibitor. We have also observed that CMM patients who are non-responders to immunotherapy have higher basal mRNA levels of MTH1 and other DNA repair genes. We are currently validating if this holds true at the protein levels as well. Conclusions: We suggest that MTH1 has an impact on response to immunotherapy and inhibition of MTH1 might be an attractive strategy to partially overcome resistance to immunotherapy and as an alternate strategy for treatment of CMM patients independent of BRAF/NRAS mutational status. Legal entity responsible for the study: Ulrika Warpman Berglund. Funding: Swedish Cancer Society, Knut and Alice Wallenberg foundation, The Swedish Research Council, Torsten and Ragnar Söderberg Foundation, The Swedish Foundation for Strategic Research. Disclosure: H. Gad: Shareholder / Stockholder / Stock options: Oxcia AB. L. Bräutigam: Shareholder / Stockholder / Stock options: Oxcia AB. L. Pudelko: Shareholder / Stockholder / Stock options: Oxcia AB. I. Almlöf: Shareholder / Stockholder / Stock options: Oxcia AB. T. Helleday: Shareholder / Stockholder / Stock options: Oxcia AB; Licensing / Royalties, Officer / Board of Directors: Thomas Helleday Foundation. U.W. Berglund: Shareholder / Stockholder / Stock options: Oxcia AB; Officer / Board of Directors: Thomas Helleday Foundation. All other authors have declared no conflicts of interest.