Activity of axial spondyloarthritis after one year of anti-tumor necrosis factor therapy among patients with inflammatory bowel diseases.

The disease activity of axSpA after initiating anti-TNF agents for inflammatory bowel diseases (IBD) is poorly understood. We sought to examine the disease activity of axial spondyloarthritis (axSpA) after initiation of anti-tumor necrosis factor (TNF) agents among patients with IBD. This retrospective cohort study included adults with IBD and axSpA who initiated anti-TNF agents between 1/1/2012-10/1/2021 at a large academic center. The primary outcome was symptom resolution (SR) of axSpA at 12 months ("0/10 pain" or "no pain" or "controlled pain" with no morning stiffness and no use of daily NSAIDs). The secondary outcome was clinical remission (CR) of IBD at 12 months (simple clinical colitis activity index <3, Harvey-Bradshaw Index <5, or provider assessment with no use of oral/IV steroids for 30 days). Associations between baseline characteristics and SR of axSpA were examined using logistic regression. 82 patients with axSpA and IBD initiated anti-TNF agents. At 12 months, 52% and 74% achieved SR of axSpA and CR of IBD, respectively. IBD duration <5 years (OR 3.0, 95% CI 1.2-7.5) and adalimumab use (reference: all other anti-TNFs; OR 2.7, 95% CI 1.002-7.1) were associated with SR of axSpA at 12 months. 52% of patients with axSpA and IBD achieved SR of axSpA at 12 months after initiating anti-TNF therapy. Shorter disease duration and adalimumab use may be associated with higher odds of SR. Larger studies are needed to confirm these findings, examine additional clinical predictors of SR, and identify more effective therapeutics for this population.

Systematic identification of anticancer drug targets reveals a nucleus-to-mitochondria ROS-sensing pathway.

Multiple anticancer drugs have been proposed to cause cell death, in part, by increasing the steady-state levels of cellular reactive oxygen species (ROS). However, for most of these drugs, exactly how the resultant ROS function and are sensed is poorly understood. It remains unclear which proteins the ROS modify and their roles in drug sensitivity/resistance. To answer these questions, we examined 11 anticancer drugs with an integrated proteogenomic approach identifying not only many unique targets but also shared ones-including ribosomal components, suggesting common mechanisms by which drugs regulate translation. We focus on CHK1 that we find is a nuclear H2O2 sensor that launches a cellular program to dampen ROS. CHK1 phosphorylates the mitochondrial DNA-binding protein SSBP1 to prevent its mitochondrial localization, which in turn decreases nuclear H2O2. Our results reveal a druggable nucleus-to-mitochondria ROS-sensing pathway-required to resolve nuclear H2O2 accumulation and mediate resistance to platinum-based agents in ovarian cancers.

Identification of chemotherapy targets reveals a nucleus-to-mitochondria ROS sensing pathway.

Multiple chemotherapies are proposed to cause cell death in part by increasing the steady-state levels of cellular reactive oxygen species (ROS). However, for most of these drugs exactly how the resultant ROS function and are sensed is poorly understood. In particular, it's unclear which proteins the ROS modify and their roles in chemotherapy sensitivity/resistance. To answer these questions, we examined 11 chemotherapies with an integrated proteogenomic approach identifying many unique targets for these drugs but also shared ones including ribosomal components, suggesting one mechanism by which chemotherapies regulate translation. We focus on CHK1 which we find is a nuclear H 2 O 2 sensor that promotes an anti-ROS cellular program. CHK1 acts by phosphorylating the mitochondrial-DNA binding protein SSBP1, preventing its mitochondrial localization, which in turn decreases nuclear H 2 O 2 . Our results reveal a druggable nucleus-to-mitochondria ROS sensing pathway required to resolve nuclear H 2 O 2 accumulation, which mediates resistance to platinum-based chemotherapies in ovarian cancers.

NRF2 activation induces NADH-reductive stress, providing a metabolic vulnerability in lung cancer.

Multiple cancers regulate oxidative stress by activating the transcription factor NRF2 through mutation of its negative regulator, KEAP1. NRF2 has been studied extensively in KEAP1-mutant cancers; however, the role of this pathway in cancers with wild-type KEAP1 remains poorly understood. To answer this question, we induced NRF2 via pharmacological inactivation of KEAP1 in a panel of 50+ non-small cell lung cancer cell lines. Unexpectedly, marked decreases in viability were observed in >13% of the cell lines-an effect that was rescued by NRF2 ablation. Genome-wide and targeted CRISPR screens revealed that NRF2 induces NADH-reductive stress, through the upregulation of the NAD+-consuming enzyme ALDH3A1. Leveraging these findings, we show that cells treated with KEAP1 inhibitors or those with endogenous KEAP1 mutations are selectively vulnerable to Complex I inhibition, which impairs NADH oxidation capacity and potentiates reductive stress. Thus, we identify reductive stress as a metabolic vulnerability in NRF2-activated lung cancers.