PUBLICATION
AXL and CAV-1 play a role for MTH1 inhibitor TH1579 sensitivity in cutaneous malignant melanoma
- Authors
- Das, I., Gad, H., Bräutigam, L., Pudelko, L., Tuominen, R., Höiom, V., Almlöf, I., Rajagopal, V., Hansson, J., Helleday, T., Egyházi Brage, S., Warpman Berglund, U.
- ID
- ZDB-PUB-200111-2
- Date
- 2020
- Source
- Cell death and differentiation 27(7): 2081-2098 (Journal)
- Registered Authors
- Bräutigam, Lars, Helleday, Thomas
- Keywords
- none
- MeSH Terms
-
- Gene Expression Regulation, Neoplastic/drug effects
- Cell Survival/drug effects
- Melanoma/drug therapy*
- Melanoma/genetics
- Melanoma/pathology
- Cell Line, Tumor
- Vemurafenib/pharmacology
- Gene Silencing/drug effects
- Phosphoric Monoester Hydrolases/antagonists & inhibitors*
- Phosphoric Monoester Hydrolases/genetics
- Phosphoric Monoester Hydrolases/metabolism
- Proto-Oncogene Proteins B-raf/genetics
- Models, Biological
- Membrane Proteins/genetics
- Mutation/genetics
- Pyrimidines/pharmacology
- Pyrimidines/therapeutic use*
- Skin Neoplasms/drug therapy*
- Skin Neoplasms/genetics
- Skin Neoplasms/pathology
- Reactive Oxygen Species/metabolism
- Zebrafish
- DNA Repair Enzymes/antagonists & inhibitors*
- DNA Repair Enzymes/genetics
- DNA Repair Enzymes/metabolism
- Caveolin 1/metabolism*
- Proto-Oncogene Proteins/metabolism*
- DNA Damage
- GTP Phosphohydrolases/genetics
- Apoptosis/drug effects
- Mitosis/drug effects
- Receptor Protein-Tyrosine Kinases/metabolism*
- Humans
- Animals
- Survival Analysis
- PubMed
- 31919461 Full text @ Cell Death Differ.
Citation
Das, I., Gad, H., Bräutigam, L., Pudelko, L., Tuominen, R., Höiom, V., Almlöf, I., Rajagopal, V., Hansson, J., Helleday, T., Egyházi Brage, S., Warpman Berglund, U. (2020) AXL and CAV-1 play a role for MTH1 inhibitor TH1579 sensitivity in cutaneous malignant melanoma. Cell death and differentiation. 27(7):2081-2098.
Abstract
Cutaneous malignant melanoma (CMM) is the deadliest form of skin cancer and clinically challenging due to its propensity to develop therapy resistance. Reactive oxygen species (ROS) can induce DNA damage and play a significant role in CMM. MTH1 protein protects from ROS damage and is often overexpressed in different cancer types including CMM. Herein, we report that MTH1 inhibitor TH1579 induced ROS levels, increased DNA damage responses, caused mitotic arrest and suppressed CMM proliferation leading to cell death both in vitro and in an in vivo xenograft CMM zebrafish disease model. TH1579 was more potent in abrogating cell proliferation and inducing cell death in a heterogeneous co-culture setting when compared with CMM standard treatments, vemurafenib or trametinib, showing its broad anticancer activity. Silencing MTH1 alone exhibited similar cytotoxic effects with concomitant induction of mitotic arrest and ROS induction culminating in cell death in most CMM cell lines tested, further emphasizing the importance of MTH1 in CMM cells. Furthermore, overexpression of receptor tyrosine kinase AXL, previously demonstrated to contribute to BRAF inhibitor resistance, sensitized BRAF mutant and BRAF/NRAS wildtype CMM cells to TH1579. AXL overexpression culminated in increased ROS levels in CMM cells. Moreover, silencing of a protein that has shown opposing effects on cell proliferation, CAV-1, decreased sensitivity to TH1579 in a BRAF inhibitor resistant cell line. AXL-MTH1 and CAV-1-MTH1 mRNA expressions were correlated as seen in CMM clinical samples. Finally, TH1579 in combination with BRAF inhibitor exhibited a more potent cell killing effect in BRAF mutant cells both in vitro and in vivo. In summary, we show that TH1579-mediated efficacy is independent of BRAF/NRAS mutational status but dependent on the expression of AXL and CAV-1.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping