ZFIN ID: ZDB-PUB-200111-2
AXL and CAV-1 play a role for MTH1 inhibitor TH1579 sensitivity in cutaneous malignant melanoma
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.
Date: 2020
Source: Cell death and differentiation   27(7): 2081-2098 (Journal)
Registered Authors: Helleday, Thomas
Keywords: none
MeSH Terms:
  • Animals
  • Apoptosis/drug effects
  • Caveolin 1/metabolism*
  • Cell Line, Tumor
  • Cell Survival/drug effects
  • DNA Damage
  • DNA Repair Enzymes/antagonists & inhibitors*
  • DNA Repair Enzymes/genetics
  • DNA Repair Enzymes/metabolism
  • GTP Phosphohydrolases/genetics
  • Gene Expression Regulation, Neoplastic/drug effects
  • Gene Silencing/drug effects
  • Humans
  • Melanoma/drug therapy*
  • Melanoma/genetics
  • Melanoma/pathology
  • Membrane Proteins/genetics
  • Mitosis/drug effects
  • Models, Biological
  • Mutation/genetics
  • Phosphoric Monoester Hydrolases/antagonists & inhibitors*
  • Phosphoric Monoester Hydrolases/genetics
  • Phosphoric Monoester Hydrolases/metabolism
  • Proto-Oncogene Proteins/metabolism*
  • Proto-Oncogene Proteins B-raf/genetics
  • Pyrimidines/pharmacology
  • Pyrimidines/therapeutic use*
  • Reactive Oxygen Species/metabolism
  • Receptor Protein-Tyrosine Kinases/metabolism*
  • Skin Neoplasms/drug therapy*
  • Skin Neoplasms/genetics
  • Skin Neoplasms/pathology
  • Survival Analysis
  • Vemurafenib/pharmacology
  • Zebrafish
PubMed: 31919461 Full text @ Cell Death Differ.
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.