PIKfyve: a lipid kinase target for COVID-19, cancer and neurodegenerative disorders.
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ABSTRACT:
SUBMITTER: Huang PT
PROVIDER: S-EPMC9166417 | biostudies-literature | 2021 Oct
REPOSITORIES: biostudies-literature
Publications
PIKfyve: a lipid kinase target for COVID-19, cancer and neurodegenerative disorders.
Huang Pei-Tzu PT Einav Shirit S Asquith Christopher R M CRM
Nature reviews. Drug discovery 20211001 10
Similar Datasets
Project description:The cellular cytotoxicity of APY0201, a PIKfyve inhibitor, against multiple myeloma was initially identified in an unbiased in vitro chemical library screen. The activity of APY0201 was confirmed in all 25 cell lines tested and in 40% of 100 ex vivo patient-derived primary samples, with increased activity in primary samples harboring trisomies and lacking t(11;14). The broad anti-multiple myeloma activity of PIKfyve inhibitors was further demonstrated in confirmatory screens and showed the superior potency of APY0201 when compared to the PIKfyve inhibitors YM201636 and apilimod, with a mid-point half maximal effective concentration (EC50) at nanomolar concentrations in, respectively, 65%, 40%, and 5% of the tested cell lines. Upregulation of genes in the lysosomal pathway and increased cellular vacuolization were observed in vitro following APY0201 treatment, although these cellular effects did not correlate well with responsiveness. We confirm that PIKfyve inhibition is associated with activation of the transcription factor EB, a master regulator of lysosomal biogenesis and autophagy. Furthermore, we established an assay measuring autophagy as a predictive marker of APY0201 sensitivity. Overall, these findings indicate promising activity of PIKfyve inhibitors secondary to disruption of autophagy in multiple myeloma and suggest a strategy to enrich for likely responders.
| S-EPMC7271606 | biostudies-literature
Project description:Despite the remarkable clinical success of immunotherapies in a subset of cancer patients, many fail to respond to treatment and exhibit resistance. Here, we found that genetic or pharmacologic inhibition of the lipid kinase PIKfyve, a regulator of autophagic flux and lysosomal biogenesis, upregulated surface expression of major histocompatibility complex class I (MHC-I) in cancer cells via impairing autophagic flux, resulting in enhanced cancer cell killing mediated by CD8+ T cells. Genetic depletion or pharmacologic inhibition of PIKfyve elevated tumor-specific MHC-I surface expression, increased intratumoral functional CD8+ T cells, and slowed tumor progression in multiple syngeneic mouse models. Importantly, enhanced antitumor responses by Pikfyve-depletion were CD8+ T cell- and MHC-I-dependent, as CD8+ T cell depletion or B2m knockout rescued tumor growth. Furthermore, PIKfyve inhibition improved response to immune checkpoint blockade (ICB), adoptive cell therapy, and a therapeutic vaccine. High expression of PIKFYVE was also predictive of poor response to ICB and prognostic of poor survival in ICB-treated cohorts. Collectively, our findings show that targeting PIKfyve enhances immunotherapies by elevating surface expression of MHC-I in cancer cells, and PIKfyve inhibitors have potential as agents to increase immunotherapy response in cancer patients.
| S-EPMC10710078 | biostudies-literature
Project description:Emerging evidence has suggested a close correlation between COVID-19 and neurodegenerative disorders. However, whether there exists a causal association and the effect direction remains unknown. To examine the causative role of COVID-19 in the risk of neurodegenerative disorders, we estimated their genetic correlation, and then conducted a two-sample Mendelian randomization analysis using summary statistics from genome-wide association studies of susceptibility, hospitalization, and severity of COVID-19, as well as six major neurodegenerative disorders including Alzheimer's disease (AD), amyotrophic lateral sclerosis, frontotemporal dementia, Lewy body dementia, multiple sclerosis, and Parkinson's disease. We identified a significant and positive genetic correlation between hospitalization of COVID-19 and AD (genetic correlation: 0.23, P = 8.36E-07). Meanwhile, hospitalization of COVID-19 was significantly associated with a higher risk of AD (OR: 1.02, 95% CI: 1.01-1.03, P: 1.19E-03). Consistently, susceptibility (OR: 1.05, 95% CI: 1.01-1.09, P: 9.30E-03) and severity (OR: 1.01, 95% CI: 1.00-1.02, P: 0.012) of COVID-19 were nominally associated with higher risk of AD. The results were robust under all sensitivity analyses. These results demonstrated that COVID-19 could increase the risk of AD. Future development of preventive or therapeutic interventions could attach importance to this to alleviate the complications of COVID-19.
| S-EPMC9281279 | biostudies-literature
Project description: Not available
| EMPIAR-10578 | biostudies-other
Project description:The phosphoinositide kinase PIKfyve has emerged as a new potential therapeutic target in various cancers. However, limited clinical progress has been achieved with PIKfyve inhibitors. Here, we report the discovery of a first-in-class PIKfyve degrader 12d (PIK5-12d) by employing the proteolysis-targeting chimera approach. PIK5-12d potently degraded PIKfyve protein with a DC50 value of 1.48 nM and a Dmax value of 97.7% in prostate cancer VCaP cells. Mechanistic studies revealed that it selectively induced PIKfyve degradation in a VHL- and proteasome-dependent manner. PIKfyve degradation by PIK5-12d caused massive cytoplasmic vacuolization and blocked autophagic flux in multiple prostate cancer cell lines. Importantly, PIK5-12d was more effective in suppressing the growth of prostate cancer cells than the parent inhibitor and exerted prolonged inhibition of downstream signaling. Further, intraperitoneal administration of PIK5-12d exhibited potent PIKfyve degradation and suppressed tumor proliferation in vivo. Overall, PIK5-12d is a valuable chemical tool for exploring PIKfyve-based targeted therapy.
| S-EPMC10510382 | biostudies-literature
Project description:Lysosomes receive and degrade cargo from endocytosis, phagocytosis and autophagy. They also play an important role in sensing and instructing cells on their metabolic state. The lipid kinase PIKfyve generates phosphatidylinositol-3,5-bisphosphate to modulate lysosome function. PIKfyve inhibition leads to impaired degradative capacity, ion dysregulation, abated autophagic flux and a massive enlargement of lysosomes. Collectively, this leads to various physiological defects, including embryonic lethality, neurodegeneration and overt inflammation. The reasons for such drastic lysosome enlargement remain unclear. Here, we examined whether biosynthesis and/or fusion-fission dynamics contribute to swelling. First, we show that PIKfyve inhibition activates TFEB, TFE3 and MITF, enhancing lysosome gene expression. However, this did not augment lysosomal protein levels during acute PIKfyve inhibition, and deletion of TFEB and/or related proteins did not impair lysosome swelling. Instead, PIKfyve inhibition led to fewer but enlarged lysosomes, suggesting that an imbalance favouring lysosome fusion over fission causes lysosome enlargement. Indeed, conditions that abated fusion curtailed lysosome swelling in PIKfyve-inhibited cells.
| S-EPMC6031331 | biostudies-literature
Project description:The cellular cytotoxicity of APY0201, a PIKfyve inhibitor, against multiple myeloma was initially identified in an unbiased in vitro chemical library screen. Activity was confirmed in all 25 cell lines tested and 40% of 100 ex vivo patient derived primary samples, and positively correlated with samples harboring trisomies and inversely related to t(11;14). The broad anti- multiple myeloma activity of PIKfyve inhibitors was further demonstrated in confirmatory screens and showed the superior potency of APY0201 when compared to the PIKfyve inhibitors YM201636 and apilimod, with a mid-point EC50 at nanomolar concentrations respectively in 65%, 40%, and 5% of the tested cell lines. An up-regulation of genes in the lysosomal pathway and increased cellular vacuolization was observed in vitro in cell lines following APY0201 treatment however this cellular response did not correlate well with responsiveness. We confirm that PIKfyve inhibition is associated with activation of the transcription factor EB, a master regulator of lysosomal biogenesis and autophagy. Furthermore, we established an assay measuring autophagy as a predictive marker of APY0201 sensitivity. Overall, these findings suggest promising activity of PIKfyve inhibitors secondary to disruption of autophagy in multiple myeloma and a strategy to enrich for likely responders.
2019-09-19 | GSE134598 | GEO
Project description:Metformin has been used for treating diabetes mellitus since the late 1950s. In addition to its antihyperglycemic activity, it was shown to be a potential drug candidate for treating a range of other diseases that include various cancers, cardiovascular diseases, diabetic kidney disease, neurodegenerative diseases, renal diseases, obesity, inflammation, COVID-19 in diabetic patients, and aging. In this review, we focus on the important aspects of mitochondrial dysfunction in energy metabolism and cell death with their gatekeeper VDAC1 (voltage-dependent anion channel 1) as a possible metformin target, and summarize metformin's effects in several diseases and gut microbiota. We question how the same drug can act on diseases with opposite characteristics, such as increasing apoptotic cell death in cancer, while inhibiting it in neurodegenerative diseases. Interestingly, metformin's adverse effects in many diseases all show VDAC1 involvement, suggesting that it is a common factor in metformin-affecting diseases. The findings that metformin has an opposite effect on various diseases are consistent with the fact that VDAC1 controls cell life and death, supporting the idea that it is a target for metformin.
| S-EPMC8521008 | biostudies-literature
Project description:The PIKfyve inhibitor apilimod is currently undergoing clinical trials for treatment of COVID-19. However, although apilimod might prevent viral invasion by inhibiting host cell proteases, the same proteases are critical for antigen presentation leading to T cell activation and there is good evidence from both in vitro studies and the clinic that apilimod blocks antiviral immune responses. We therefore warn that the immunosuppression observed in many COVID-19 patients might be aggravated by apilimod.
| S-EPMC7824419 | biostudies-literature
Project description:Pancreatic ductal adenocarcinoma (PDAC) subsists in a nutrient-deregulated microenvironment, making it particularly susceptible to treatments that interfere with cancer metabolism12. For example, PDAC utilizes and is dependent on high levels of autophagy and other lysosomal processes3-5. Although targeting these pathways has shown potential in preclinical studies, progress has been hampered by the challenge of identifying and characterizing favorable targets for drug development6. Here, we characterize PIKfyve, a lipid kinase integral to lysosomal functioning7, as a novel and targetable vulnerability in PDAC. In human patient and murine PDAC samples, we discovered that PIKFYVE is overexpressed in PDAC cells compared to adjacent normal cells. Employing a genetically engineered mouse model, we established the essential role of PIKfyve in PDAC progression. Further, through comprehensive metabolic analyses, we found that PIKfyve inhibition obligated PDAC to upregulate de novo lipid synthesis, a relationship previously undescribed. PIKfyve inhibition triggered a distinct lipogenic gene expression and metabolic program, creating a dependency on de novo lipid metabolism pathways, by upregulating genes such as FASN and ACACA. In PDAC, the KRAS-MAPK signaling pathway is a primary driver of de novo lipid synthesis, specifically enhancing FASN and ACACA levels. Accordingly, the simultaneous targeting of PIKfyve and KRAS-MAPK resulted in the elimination of tumor burden in a syngeneic orthotopic model and tumor regression in a xenograft model of PDAC. Taken together, these studies suggest that disrupting lipid metabolism through PIKfyve inhibition induces synthetic lethality in conjunction with KRAS-MAPK-directed therapies for PDAC.
| S-EPMC10983929 | biostudies-literature