bims-meluca 2019-12-29 papers

J Clin Invest. 2019 Dec 24. pii: 124049. [Epub ahead of print]

Suppression of the SLC7A11/glutathione axis causes synthetic lethality in KRAS-mutant lung adenocarcinoma.

Kewen Hu, Kun Li, Jing Lv, Jie Feng, Jing Chen, Haigang Wu, Feixiong Cheng, Wenhao Jiang, Jieqiong Wang, Haixiang Pei, Paul J Chiao, Zhenyu Cai, Yihua Chen, Mingyao Liu, Xiufeng Pang.

Oncogenic KRAS is a major driver in lung adenocarcinoma (LUAD) that has yet to be therapeutically conquered. Here we report that the SLC7A11/glutathione axis displays metabolic synthetic lethality with oncogenic KRAS. Through metabolomics approaches, we found that mutationally activated KRAS strikingly increased the intracellular cystine level and glutathione biosynthesis. SLC7A11, a cystine/glutamate antiporter conferring specificity for cystine uptake, was overexpressed in patients with KRAS-mutant LUAD and showed positive association with tumor progression. Furthermore, SLC7A11 inhibition either by genetic depletion or pharmacological inhibition by sulfasalazine resulted in selective killing across a panel of KRAS-mutant cancer cells in vitro and tumor growth inhibition in vivo, suggesting the functionality and specificity of SLC7A11 as a therapeutic target. Importantly, we further identified a potent SLC7A11 inhibitor, HG106 that markedly decreased cystine uptake and intracellular glutathione biosynthesis. Furthermore, HG106 exhibited selective cytotoxicity towards KRAS-mutant cells by increasing oxidative stress- and endoplasmic reticulum stress-mediated cell apoptosis. Of note, treatment of KRAS-mutant LUAD with HG106 in several lung cancer preclinical mouse models led to marked tumor suppression and prolonged mouse survival. Overall, our findings reveal that KRAS-mutant LUAD cells are vulnerable to SLC7A11 inhibition, providing promising therapeutic approaches to the treatment of this currently incurable disease.

Keywords: Cancer; Drug therapy; Oncology

DOI: https://doi.org/10.1172/JCI124049

ACS Chem Biol. 2019 Dec 24.

Target Discovery of Selective Non-Small-Cell Lung Cancer Toxins Reveals Inhibitors of Mitochondrial Complex I.

Nikhil Madhusudhan, Bin Hu, Prashant Mishra, Josè F Calva-Moreno, Khushbu Patel, Richard Boriack, Joseph M Ready, Deepak Nijhawan.

Selective toxicity among cancer cells of the same lineage is a hallmark of targeted therapies. As such, identifying compounds that impair proliferation of a subset of non-small-cell lung cancer (NSCLC) cell lines represents one strategy to discover new drugs for lung cancer. Previously, phenotypic screens of 202 103 compounds led to the identification of 208 selective NSCLC toxins ( McMillan , E. A. , Cell , 2018 , 173 , 864 ). The mechanism of action for the majority of these compounds remains unknown. Here, we discovered the target for a series of quinazoline diones (QDC) that demonstrate selective toxicity among 96 NSCLC lines. Using photoreactive probes, we found that the QDC binds to both mitochondrial complex I of the electron transport chain and hydroxyacyl CoA dehydrogenase subunit alpha (HADHA), which catalyzes long-chain fatty acid oxidation. Inhibition of complex I is the on-target activity for QDC, while binding to HADHA is off-target. The sensitivity profile of the QDC across NSCLC lines correlated with the sensitivity profiles of six additional structurally distinct compounds. The antiproliferative activity of these compounds is also the consequence of binding to mitochondrial complex I, reflecting significant structural diversity among complex I inhibitors. Small molecules targeting complex I are currently in clinical development for the treatment of cancer. Our results highlight complex I as a target in NSCLC and report structurally diverse scaffolds that inhibit complex I.

DOI: https://doi.org/10.1021/acschembio.9b00734

Ann Nutr Metab. 2019 Dec 19. 1-8

Lean Body Mass and Endocrine Status But Not Age Are Determinants of Resting Energy Expenditure in Patients with Non-Small Cell Lung Cancer.

Guillaume Ulmann, Anne Jouinot, Camille Tlemsani, Emmanuel Curis, Isabelle Kousignian, Nathalie Neveux, Jean-Philippe Durand, François Goldwasser, Luc Cynober, Jean-Pascal De Bandt.

BACKGROUND: Cancer and aging are both frequently associated with malnutrition, a factor of poor prognosis. In adult cancer patients, this may be related in part to impaired energy metabolism, with higher than predicted resting energy expenditure (REE) in about 50% of patients. We hypothesized that frequently impaired energy metabolism in elderly patients could potentiate cancer-associated hypermetabolism, further promoting risk of malnutrition.
OBJECTIVE: To study the hypermetabolic response to cancer in a predominantly aged population and the potential underlying determinants.
METHODS: This was a cross-sectional exploratory study in patients with non-small-cell lung cancer. REE was measured by indirect calorimetry. Body composition was determined from a single CT scan imaging at L3 level. Endocrine, inflammatory, nutritional and metabolic status were evaluated.
RESULTS: Twenty-seven patients, of median age 68 years (range 32-81) completed the study. In this population, mean measured REE was 7.5% higher than calculated REE. Sex and weight accounted for about 51% of REE variations, whereas age accounted only for 4%. However, these parameters did not explain the REE-to-lean body mass (LBM) ratio variations, suggesting that they influenced REE only through their effect on LBM. Among the other parameters evaluated, only the thyroid-stimulating hormone and interleukin-6 plasma levels appeared to have an influence on REE. The study of the consequences of this increase in REE-to-LBM ratio showed a growing inability of patients to meet their energy needs but showed no effect on nutritional markers such as transthyretin.
CONCLUSIONS: The results of this pilot study suggest that in our population, age was not an important factor of REE. The elevated energy metabolism was associated with patients' failure to increase their energy intakes sufficiently, which can contribute to the development of cachexia.
CLINICAL TRIAL: This trial is registered at clinicaltrials.gov under NCT0314.

Keywords: Aging; Cancer; Hypermetabolism; Lean body mass; Resting energy expenditure

DOI: https://doi.org/10.1159/000504874