Chesney, J. A. | Search bioRxiv

bioRxiv2024

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

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.

cancer biology↗

bioRxiv2022

Tumor-educated monocytes suppress T cells via adenosine and depletion of adenosine in the tumor microenvironment with adenosine deaminase enzyme promotes response to immunotherapy

Although immune checkpoint inhibitor (ICI) therapy has provided robust results in many cancer types such as melanoma and lung cancer, a large percentage of patients remain unresponsive to this therapy. Emerging evidence strongly suggests that one of the contributing factors in ICI resistance is monocytic myeloid derived suppressor cells (M-MDSCs) that accumulate in late-stage cancer patients. These M-MDSCs are a subset of innate immune cells and possess potent immunosuppressive activity against T lymphocytes. Here we provide evidence of a mechanism by which CD73-expressing M-MDSCs in the tumor microenvironment (TME) exhibit superior T cell suppressor function via adenosine. We show that tumor-derived PGE2, a prostaglandin frequently found at high levels in the TME, directly induces CD73 expression in M-MDSCs by initiating a signaling pathway that is mediated by both Stat3 and CREB. The resulting CD73 overexpression induces elevated levels of adenosine, a nucleoside with strong T cell suppressive activity, culminating in the suppression of CD8+ T cell-mediated anti-tumor responses. We also show that depletion of adenosine in the TME by the repurposed drug PEGylated Adenosine Deaminase (PEG-ADA) increases CD8+ T cell anti-tumor activity and enhances response to ICI therapy in preclinical models of cancer. Our results suggest that use of PEG-ADA is a viable therapeutic option to overcome ICI therapeutic resistance in advanced cancer patients.

cell biology↗