PFKFB3 Inhibition Impairs Erlotinib-Induced Autophagy in NSCLCs

Lypova, Nadiia; Dougherty, Susan; Lanceta, Lilibeth; Chesney, Jason; Imbert-Fernandez, Yoannis

doi:10.3390/cells10071679

Cited by 14 publications

(7 citation statements)

References 67 publications

(93 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2G). These results, along with a previously published study by our group showing that PFKFB3 inhibition limits autophagy flux and results in AMPK inactivation in erlotinib-treated cells (61) provide strong evidence that inhibiting PFKFB3 can effectively limit the metabolic adaptivity of lung cancer cells when treated with targeted therapies.…”

Section: Discussionsupporting

confidence: 75%

Role of 6-Phosphofructo-2-Kinase/Fructose-2,6-Bisphosphatase-3 in Maintaining Redox Homeostasis and DNA Repair in Non-Small Cell Lung Cancers Under EGFR-Targeting Therapy

Lypova,

Dougherty,

Clem

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

The efficacy of FDA-approved tyrosine kinase inhibitors (TKIs) targeting EGFR is limited due to the persistence of drug-tolerant cell populations, leading to therapy resistance. Non-genetic mechanisms, such as metabolic rewiring, play a significant role in driving lung cancer cells into the drug-tolerant state, allowing them to persist under continuous drug treatment. This study aimed to investigate the impact of the glycolytic regulator 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3) on the metabolic adaptivity of lung cancer cells to EGFR TKI therapies. Using two EGFR-driven non-small cell lung cancer cell lines, PC9 and HCC827, we analyzed metabolic changes in cells exposed to EGFR inhibitors and evaluated the effect of PFKFB3 inhibition on metabolic adaptations during TKI treatment. Our results indicate that PFKFB3-mediated glycolysis sustains ATP production upon TKI treatment. Metabolomics studies revealed that PFKFB3 inhibition in TKI-treated cells limits glucose utilization in glycolysis, TCA cycle, and polyol pathway. Additionally, we show that pharmacological inhibition of PFKFB3 overcomes TKI-driven redox capacity by diminishing the expression of glutathione peroxidase 4 (GPX4), which in turn, exacerbates oxidative stress. Our study also revealed that PFKFB3 contributes to DNA oxidation and damage by controlling the expression of DNA-glycosylases involved in base excision repair. In TKI-treated cells, PFKFB3 inhibition reduced ATM expression and limited DNA damage repair, increasing sensitivity to DNA integrity insults.In summary, our results suggest that inhibiting PFKFB3 can be an effective strategy to eradicate cancer cells surviving under EGFR-TKI therapy before they enter the drug-resistant state.STATEMENT OF IMPLICATIONTargeting PFKFB3 can improve the efficacy of EGFR-targeting TKIs by restricting non-genetic adaptations embraced by drug-tolerant cells.

show abstract

Section: Discussionsupporting

confidence: 75%

Role of 6-Phosphofructo-2-Kinase/Fructose-2,6-Bisphosphatase-3 in Maintaining Redox Homeostasis and DNA Repair in Non-Small Cell Lung Cancers Under EGFR-Targeting Therapy

Lypova,

Dougherty,

Clem

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Although we hypothesize that ΔΨ m -dependent mitochondrial over-enrichment of MitoQ is the primary mechanism underlying the synergy between MitoQ and erlotinib, we also appreciate additional possibilities. For example, MitoQ can induce mitophagy via the PTEN-induced kinase 1/Parkin RBR E3 ubiquitin-protein ligase pathway[ 65 , 66 ], and erlotinib can induce autophagy through p53 nuclear translocation, AMP-activated protein kinase activation, and mTOR suppression[ 67 , 68 ]. Therefore, it is also possible that MitoQ and erlotinib synergize in the context of autophagic cell death.…”

Section: Discussionmentioning

confidence: 99%

Erlotinib combination with a mitochondria-targeted ubiquinone effectively suppresses pancreatic cancer cell survival

Leung,

Chen,

Sari

et al. 2024

World J Gastroenterol

View full text Add to dashboard Cite

BACKGROUND Pancreatic cancer is a leading cause of cancer-related deaths. Increased activity of the epidermal growth factor receptor (EGFR) is often observed in pancreatic cancer, and the small molecule EGFR inhibitor erlotinib has been approved for pancreatic cancer therapy by the food and drug administration. Nevertheless, erlotinib alone is ineffective and should be combined with other drugs to improve therapeutic outcomes. We previously showed that certain receptor tyrosine kinase inhibitors can increase mitochondrial membrane potential (Δψm), facilitate tumor cell uptake of Δψm-sensitive agents, disrupt mitochondrial homeostasis, and subsequently trigger tumor cell death. Erlotinib has not been tested for this effect. AIM To determine whether erlotinib can elevate Δψm and increase tumor cell uptake of Δψm-sensitive agents, subsequently triggering tumor cell death. METHODS Δψm-sensitive fluorescent dye was used to determine how erlotinib affects Δψm in pancreatic adenocarcinoma (PDAC) cell lines. The viability of conventional and patient-derived primary PDAC cell lines in 2D- and 3D cultures was measured after treating cells sequentially with erlotinib and mitochondria-targeted ubiquinone (MitoQ), a Δψm-sensitive MitoQ. The synergy between erlotinib and MitoQ was then analyzed using SynergyFinder 2.0. The preclinical efficacy of the two-drug combination was determined using immune-compromised nude mice bearing PDAC cell line xenografts. RESULTS Erlotinib elevated Δψm in PDAC cells, facilitating tumor cell uptake and mitochondrial enrichment of Δψm-sensitive agents. MitoQ triggered caspase-dependent apoptosis in PDAC cells in culture if used at high doses, while erlotinib pretreatment potentiated low doses of MitoQ. SynergyFinder suggested that these drugs synergistically induced tumor cell lethality. Consistent with in vitro data, erlotinib and MitoQ combination suppressed human PDAC cell line xenografts in mice more effectively than single treatments of each agent. CONCLUSION Our findings suggest that a combination of erlotinib and MitoQ has the potential to suppress pancreatic tumor cell viability effectively.

show abstract

“…Erlotinib induced autophagy to promote erlotinib resistance via 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) in NSCLCs [ 122 ]. Wingless-related integration site 5A (Wnt5A)-induced autophagy mediated doxorubicin resistance in osteosarcoma cells [ 123 ].…”

Section: Role Of Autophagy In Senescencementioning

confidence: 99%

The Potential of Senescence as a Target for Developing Anticancer Therapy

Shim

Jeoung

2023

IJMS

View full text Add to dashboard Cite

Senescence occurs in response to various stimuli. Senescence has attracted attention because of its potential use in anticancer therapy as it plays a tumor-suppressive role. It also promotes tumorigeneses and therapeutic resistance. Since senescence can induce therapeutic resistance, targeting senescence may help to overcome therapeutic resistance. This review provides the mechanisms of senescence induction and the roles of the senescence-associated secretory phenotype (SASP) in various life processes, including therapeutic resistance and tumorigenesis. The SASP exerts pro-tumorigenic or antitumorigenic effects in a context-dependent manner. This review also discusses the roles of autophagy, histone deacetylases (HDACs), and microRNAs in senescence. Many reports have suggested that targeting HDACs or miRNAs could induce senescence, which, in turn, could enhance the effects of current anticancer drugs. This review presents the view that senescence induction is a powerful method of inhibiting cancer cell proliferation.

show abstract

PFKFB3 Inhibition Impairs Erlotinib-Induced Autophagy in NSCLCs

Cited by 14 publications

References 67 publications

Role of 6-Phosphofructo-2-Kinase/Fructose-2,6-Bisphosphatase-3 in Maintaining Redox Homeostasis and DNA Repair in Non-Small Cell Lung Cancers Under EGFR-Targeting Therapy

Role of 6-Phosphofructo-2-Kinase/Fructose-2,6-Bisphosphatase-3 in Maintaining Redox Homeostasis and DNA Repair in Non-Small Cell Lung Cancers Under EGFR-Targeting Therapy

Erlotinib combination with a mitochondria-targeted ubiquinone effectively suppresses pancreatic cancer cell survival

The Potential of Senescence as a Target for Developing Anticancer Therapy

Contact Info

Product

Resources

About