AXL and CAV-1 play a role for MTH1 inhibitor TH1579 sensitivity in cutaneous malignant melanoma

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 coculture 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.

Tagitinin C induces ferroptosis through PERK-Nrf2-HO-1 signaling pathway in colorectal cancer cells

“…We next investigated the effect of tagitinin C on colony formation in HCT116 cells by clonogenic cell survival assay 28 - 30 . As shown in Figure 2 A-B, tagitinin C induced a significant concentration-dependent reduction in the number of colonies after 14 days treatment.…”

Coexpression of MTH1 and PMS2 Is Associated with Advanced Disease and Disease Progression after Therapy in Melanoma

“…It is often overexpressed in various types of cancer including CMM (Wang et al, 2018). We recently reported that combining the MTH1 inhibitor TH1579 with a BRAF J o u r n a l P r e -p r o o f inhibitor further augments cell death in BRAFV600 mutant CMM cells compared to either inhibitor alone (Das et al, 2020).…”

Zebrafish Xenografts for Drug Discovery and Personalized Medicine

“…Zebrafish xenografts assays have been frequently incorporated into studies on the control of cancer growth, invasion, and migration. Components of cancer-related pathways have been altered by gene mutations [34,35], gene overexpression or knockdown [35][36][37][38][39][40][41][42], protein inactivation by antibody binding [41], pharmacological inhibition of protein function [34,36,42,43], and cell culture selection for drug resistance [32,43]. In many of these studies, zebrafish xenograft models were run in parallel with mouse models, which reported comparable results [34,[36][37][38][41][42][43].…”

“…In addition, zebrafish xenografts have enabled the study of several novel therapies, including ectopic overexpression of protein deacetylases, epigenetic modulators, VEGFR inhibitors, and inhibition of SMYD3, CDCA7, MTH1, and p38b/CK2/SET [34,42,[57][58][59].…”