Arf6 as a therapeutic target: Structure, mechanism, and inhibitors

Sun, Dejuan; Guo, Yuanyuan; Tang, Piyu; Li, Hua; Chen, Lixia

doi:10.1016/j.apsb.2023.06.008

Cited by 5 publications

(5 citation statements)

References 125 publications

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“…ARF6 has been considered as a potential therapeutic target due to its multifaceted role in cancer progression. 21 We show here that targeting ARF6 alone may not be sufficient, leading to acquired tumour resistance. Co-knockdown of TLR2 with ARF6 showed profound effects in vivo, almost abolishing tumour growth in a mouse xenograft model.…”

Section: Discussionmentioning

confidence: 74%

“…Loss of ARF6 has been studied to impair proliferation, migration and invasion, [13][14][15][16][17][18][19] which in turn has prompted the development of ARF6 inhibitor NAV-2729, 20 and is considered as a potential therapeutic target. 21 For instance, ARF6 is an inhibitor of the RLS3induced ferroptosis and a promoter of gemcitabine resistance in PDAC. 17 Additionally, ARF6 function may also act as a positive feedback loop for ERK signalling, which is fundamental in various MAPK pathway processes in cancer.…”

Section: Arf6 But Not Asap1 Downregulation Leads To Pdac Adaptationmentioning

confidence: 99%

“…Various independent studies have highlighted the role of ARF6 in drug resistance and as a result, targeting of ARF6 is now a seriously considered therapeutic strategy for breast, gastric, renal and pancreatic malignancies (reviewed by Dejuan Sun et al). 21 ARF6 with ZEB1 has been shown to confer drug resistance in breast cancer against Gemcitabine, 5-fluorouracil and Temsirolimus. 46 In renal cell carcinomas it has been linked with resistance against 5-fluorouracil.…”

Section: Tlr2-activated Nfκb Tnfα and Hypoxia Pathways Promote Tumour...mentioning

confidence: 99%

“…Loss of ARF6 has been studied to impair proliferation, migration and invasion, [13][14][15][16][17][18][19] which in turn has prompted the development of ARF6 inhibitor NAV-2729, 20 and is considered as a potential therapeutic target. 21 GTPases use effector proteins for their downstream signalling. Among others, ASAP1 (also AMAP1 or DDEF1), is a major downstream effector of ARF6 in various cancers, but particularly important in PDAC.…”

Section: Introductionmentioning

confidence: 99%

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Adaptation to ARF6-depletion in KRAS-driven PDAC is abolished by targeting TLR2

Ghose,

Das,

Urgel-Solas

et al. 2023

Preprint

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SUMMARYMetastasis is responsible for nearly 90% of all cancer-related deaths. Despite global efforts to prevent aggressive tumours, cancers such as pancreatic ductal adenocarcinoma (PDAC) are poorly diagnosed in the primary stage, resulting in lethal metastatic disease. RAS mutations are known to promote tumour spread, with mutant KRAS present in up to 90% of cases. Until recently, mutant KRAS remained untargeted and, despite the recent development of inhibitors, results show that tumour cells develop resistance. Another strategy for targeting mutant KRAS-dependent PDAC proliferation and metastasis may come from targeting the downstream effectors of KRAS. One such axis, which controls tumour proliferation, invasiveness and immune evasion, is represented by ARF6-ASAP1. Here we show that targeting ARF6 results in adaptive rewiring that can restore proliferation and invasion potential over time. Using time-series RNA and ATAC sequencing approaches, we identified TLR-dependent NFκB, TNFα and hypoxia signalling as key drivers of adaptation in ARF6-depleted KRAS-dependent PDAC. Using in vitro and in vivo assays, we show that knocking down TLR2 with ARF6 significantly reduces proliferation, migration and invasion. Taken together, our data shed light on a novel co-targeting strategy with the therapeutic potential to counteract PDAC proliferation and metastasis.GRAPHICAL SUMMARY

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Section: Discussionmentioning

confidence: 74%

Section: Arf6 But Not Asap1 Downregulation Leads To Pdac Adaptationmentioning

confidence: 99%

Section: Tlr2-activated Nfκb Tnfα and Hypoxia Pathways Promote Tumour...mentioning

confidence: 99%

“…Loss of ARF6 has been studied to impair proliferation, migration and invasion, [13][14][15][16][17][18][19] which in turn has prompted the development of ARF6 inhibitor NAV-2729, 20 and is considered as a potential therapeutic target. 21 GTPases use effector proteins for their downstream signalling. Among others, ASAP1 (also AMAP1 or DDEF1), is a major downstream effector of ARF6 in various cancers, but particularly important in PDAC.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Adaptation to ARF6-depletion in KRAS-driven PDAC is abolished by targeting TLR2

Ghose,

Das,

Urgel-Solas

et al. 2023

Preprint

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“…And nucleation occurs in the zone, which is the formation of critical‐sized, stable nuclei in a solution supersaturated with methane gas. [ 22 ] From a microscopic scale analysis, the so‐called nucleation phenomenon is the first step required for hydrate formation at the gas–liquid interface to occur under initial conditions that satisfy the pressure and temperature in the range where hydrates can be formed but no gas molecules are dissolved in water, [ 23 ] for example, as shown in Figure 5h. At the same time, the stochastic nature of hydrate nucleation leads to the inability to visibly observe the nucleation zone in the pressure–time curve in most of the experiments, for example, as shown in Figure 5a.…”

Section: Analysis Of Resultsmentioning

confidence: 99%

Experimental Investigation Into Effects of Thermodynamic Hydrate Inhibitors on Natural Gas Hydrate Synthesis in 1D Reactor

et al. 2023

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Thermodynamic hydrate inhibitors (THIs) are often used in marine gas field operations to prevent the formation of natural gas hydrate (NGH), and it is important to study the effect of THIs on hydrate synthesis characteristics. Herein, the effects of water (H2O), sodium chloride (NaCl), and ethylene glycol (EG) on NGH synthesis characteristics under different initial pressure conditions are tested using the self‐developed 1D NGH production simulation test system. The effects of each THI on the maximum synthesis rate and maximum synthesis amount of NGH are investigated using two physical quantities, peak of temperature increment and maximum gas conversion rate. The results show that the 2.65 wt% salt solution has the minimum inhibition effect on the maximum synthesis rate of NGH, and the solution with a 3:1 mixture of H2O and EG has the maximal inhibition effect on the maximum synthesis rate of NGH. When only H2O and EG or H2O and NaCl are present in the reactor, the higher the concentration of EG or NaCl, the more significant is the inhibition effect on the maximum synthesis amount of NGH.

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CD24 promotes metastasis and chemoresistance by directly targeting Arf6-ERK pathway in esophageal squamous cell carcinoma

Hong,

Xu,

et al. 2024

Cancer Letters

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Arf6 as a therapeutic target: Structure, mechanism, and inhibitors

Cited by 5 publications

References 125 publications

Adaptation to ARF6-depletion in KRAS-driven PDAC is abolished by targeting TLR2

Adaptation to ARF6-depletion in KRAS-driven PDAC is abolished by targeting TLR2

Experimental Investigation Into Effects of Thermodynamic Hydrate Inhibitors on Natural Gas Hydrate Synthesis in 1D Reactor

CD24 promotes metastasis and chemoresistance by directly targeting Arf6-ERK pathway in esophageal squamous cell carcinoma

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