Henske, E. P. | bioRxiv Science

bioRxiv2020

Mechanosensitive activation of mTORC1 mediates ventilator induced lung injury during the acute respiratory distress syndrome

Acute respiratory distress syndrome (ARDS) is a highly lethal condition that impairs lung function and causes respiratory failure. Mechanical ventilation maintains gas exchange in patients with ARDS, but exposes lung cells to physical forces that exacerbate lung injury. Our data demonstrate that mTOR complex 1 (mTORC1) is a mechanosensor in lung epithelial cells and that activation of this pathway during mechanical ventilation exacerbates lung injury. We found that mTORC1 is activated in lung epithelial cells following volutrauma and atelectrauma in mice and humanized in vitro models of the lung microenvironment. mTORC1 is also activated in lung tissue of mechanically ventilated patients with ARDS. Deletion of Tsc2, a negative regulator of mTORC1, in epithelial cells exacerbates physiologic lung dysfunction during mechanical ventilation. Conversely, treatment with rapamycin at the time mechanical ventilation is initiated prevents physiologic lung injury (i.e. decreased compliance) without altering lung inflammation or barrier permeability. mTORC1 inhibition mitigates physiologic lung injury by preventing surfactant dysfunction during mechanical ventilation. Our data demonstrate that in contrast to canonical mTORC1 activation under favorable growth conditions, activation of mTORC1 during mechanical ventilation exacerbates lung injury and inhibition of this pathway may be a novel therapeutic target to mitigate ventilator induced lung injury during ARDS.

molecular biology↗

bioRxiv2019

IMPDH inhibitors for anti-tumor therapy in tuberous sclerosis complex

Structured AbstractO_ST_ABSPurposeC_ST_ABSmTORC1 is a master regulator of anabolic cell growth and proliferation that is activated in the majority of human tumors. We recently demonstrated that elevated mTORC1 activity in cells and tumors can confer dependence on IMPDH, the rate-limiting enzyme in de novo guanylate nucleotide synthesis, to support increased ribosome biogenesis and cell viability. Pharmacological agents that inhibit IMPDH, such as mizoribine and mycophenolic acid (CellCept), are in wide clinical use as immunosuppressants. However, whether these agents can be repurposed for anti-tumor therapy requires further investigation in preclinical models, including direct comparisons to identify the best candidate(s) for advancement. Experimental DesignDistinct IMPDH inhibitors were tested on cell and mouse tumor models of tuberous sclerosis complex (TSC), a genetic tumor syndrome featuring widespread lesions with uncontrolled mTORC1 activity. Growth and viability were assessed in cells and tumors lacking the TSC2 tumor suppressor, together with drug pharmacokinetics and pharmacodynamics, target inhibition, and effects on tumor, tissue, and plasma metabolic biomarkers. ResultsMizoribine, used throughout Asia, exhibited greater selectivity in specifically targeting TSC2-deficient cells with active mTORC1 compared to the FDA-approved IMPDH inhibitors mycophenolic acid or ribavirin, or approved inhibitors of other nucleotide synthesis enzymes. In distinct tumor models, mizoribine demonstrated robust anti-tumor efficacy that is superior to mycophenolic acid, despite similar immunosuppressive effects. ConclusionsThese results provide pre-clinical rationale for repurposing mizoribine as an anti-tumor agent in tumors with active mTORC1, such as in TSC. Our findings also suggest that IMPDH inhibitors should be revisited in cancer models where MMF has shown modest efficacy. Statement of translational relevanceIMPDH inhibitors have been used clinically for decades as safe and effective immunosuppressants. Recent studies in pre-clinical tumor models establish IMPDH as a viable target for anti-tumor therapy, but the relative efficacies of approved IMPDH inhibitors in tumors have not been directly compared. Our data demonstrate a clear advantage of the IMPDH inhibitor mizoribine, used clinically throughout Asia, over the FDA-approved IMPDH inhibitor mycophenolate mofetil (or CellCept, a prodrug of mycophenolic acid) in mouse models of tuberous sclerosis complex (TSC) exhibiting mTORC1-driven tumor growth. While these IMPDH inhibitors elicit similar immunosuppressive effects, mizoribine has far superior anti-tumor activity in these models, indicating the potential for repurposing this drug for TSC and perhaps cancer treatment. We also identify the purine synthesis intermediate AICAR as an in vivo metabolic biomarker specific for effective inhibition of IMPDH with mizoribine, which can be readily detected in blood plasma shortly after mizoribine administration.

cancer biology↗