Overcoming Intrinsic Multidrug Resistance in Melanoma by Blocking the Mitochondrial Respiratory Chain of Slow-Cycling JARID1Bhigh Cells

Abstract

Summary Despite success with BRAFV600E–inhibitors, therapeutic responses in patients with metastatic melanoma are short-lived because of the acquisition of drug resistance. We identified a mechanism of intrinsic multi-drug resistance based on the survival of a tumor cell subpopulation. Treatment with various drugs, including cisplatin and vemurafenib, uniformly leads to enrichment of slow-cycling, long-term tumor-maintaining melanoma cells expressing the H3K4-demethylase JARID1B/KDM5B/PLU-1. Proteome-profiling revealed an upregulation in enzymes of mitochondrial oxidative-ATP-synthesis (OXPHOS) in this subpopulation. Inhibition of mitochondrial respiration blocked the emergence of the JARID1Bhigh subpopulation and sensitized melanoma cells to therapy, independent of their genotype. Our findings support a two-tiered approach combining anti-cancer agents that eliminate rapidly proliferating melanoma cells with inhibitors of the drug-resistant slow-cycling subpopulation.

Up‐regulated deubiquitinase USP4 plays an oncogenic role in melanoma

“…Cisplatin is a conventional chemotherapeutic agent for melanoma therapy by inducing DNA damage. However, the intrinsic pro‐survival signalling could abolish the killing efficiency and lead to cisplatin tolerance and tumour development of melanoma 23, 24. Since that USP4 played a critical role in DNA damage response,16, 17 we proposed that the intervention of USP4 may affect cisplatin‐induced cell apoptosis in melanoma.…”

Establishment of 5-Fluorouracil-resistant canine mammary tumor cell line

“…The proliferation rate of CMT7364/5-FU cells was much slower. Nowadays, the study of slow-cycling cells is rather actively (Chen et al 2012, Moore et al 2012, Roesch et al 2013). Slow-cycling cells are subpopulations of tumor cells that grow slower, at the meantime, they can exhibit resistance to chemotherapy, leading to cancer recurrence, and even have a close association with stem cells (Ishimoto et al 2010).…”

93 A stress induced early innate response causes multi-drug tolerance in melanoma

“…This suggests that IDTC formation could be a product of interrelation between multiple individual components including CD271 upregulation, histone modification and increased activity of multiple signaling pathways. Accordingly, we observed that the combined strategies including the use of HDAC, IGF1R, Pi3K/AKT inhibitors 4 and oligomycin A targeting mitochondrial survival pathways, 6 along with the primary drug, exert a higher potential to eliminate the parental population before transition into IDTCs, whereas IDTCs by themselves showed an elevated tolerance even toward these combined exposures. The study suggests that multiple factors contribute to the transition and maintenance of the IDTC state and from these observations it is tempting to speculate that the burden of signaling is distributed between multiple pathways unlike the parental BRAF mutant cells, which seem to be primarily dependent on BRAF-driven ERK signaling.…”

“…The increased CD271 expression as a characteristic marker of IDTCs suggested a potential new target that could resensitize cells, similar to what has been reported for KDM5B in eliminating a slow cycling melanoma population. 6 Indeed, stable knockdown of either CD271 (WM164 sh CD271) or KDM5B (WM164 sh KDM5B) in the parental cells increased their sensitivity to single or combination strategies compared with control short hairpin RNA (shRNA)-transduced WM164 cells exposed to single or combined treatments (Figure 5b). More durable effects were observed in the case of prolonged exposure over 12 days to different concentrations of PLX4032, whereupon the number of surviving cells was substantially reduced in WM164 shCD271 and WM164 shKDM5B cells, even at 250 and 500 nM ( Figure 5c).…”