Publications

Cells are subjected to oxidative stress during the initiation and progression of tumors, and this imposes selective pressure for cancer cells to adapt mechanisms to tolerate these conditions. Here, we examined the dependency of cancer cells on glutathione (GSH), the most abundant cellular antioxidant. While cancer cell lines displayed a broad range of sensitivities to inhibition of GSH synthesis, the majority were resistant to GSH depletion. To identify cellular pathways required for this resistance, we carried out genetic and pharmacologic screens. Both approaches revealed that inhibition of deubiquitinating enzymes (DUBs) sensitizes cancer cells to GSH depletion. Inhibition of GSH synthesis, in combination with DUB inhibition, led to an accumulation of polyubiquitinated proteins, induction of proteotoxic stress, and cell death. These results indicate that depletion of GSH renders cancer cells dependent on DUB activity to maintain protein homeostasis and cell viability and reveal a potentially exploitable vulnerability for cancer therapy.

PURPOSE

Myositis-associated interstitial lung disease (MA-ILD) is associated with increased mortality, but no prognostic model exists in this population. The ILD-GAP index was developed to predict mortality risk across all subtypes of chronic ILD. The purpose of this study was to validate the ILD-GAP risk prediction model in patients with MA-ILD.

PROCEDURES

We completed a retrospective cross-sectional study of patients enrolled in the Johns Hopkins Myositis Center database between 2006 and 2017. Cumulative mortality rates were estimated using the Kaplan-Meier test. Model calibration was determined by using standardized mortality ratios of observed versus expected deaths.

MAIN FINDINGS

179 participants with MA-ILD were included. The mean baseline percent predicted forced vital capacity was 65.2 ± 20.6%, forced expiratory volume in the first second 65.4 ± 20.4%, and carbon monoxide diffusing capacity 61.6 ± 20.0%. Thirty-two participants died (17.9%). The ILD-GAP model had poor discriminative performance and calibration.

CONCLUSIONS

The ILD-GAP risk prediction model is a poor predictor of mortality among individuals with MA-ILD. The identification of a better predictive model for MA-ILD is needed to help guide care in this patient population.