Wild-type IDH1 maintains NSCLC stemness and chemoresistance through activation of the serine biosynthetic pathway.

Tumor-initiating cells (TICs) reprogram their metabolic features to meet their bioenergetic, biosynthetic, and redox demands. Our previous study established a role for wild-type isocitrate dehydrogenase 1 (IDH1WT) as a potential diagnostic and prognostic biomarker for non-small cell lung cancer (NSCLC), but how IDH1WT modulates NSCLC progression remains elusive. Here, we report that IDH1WT activates serine biosynthesis by enhancing the expression of phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase 1 (PSAT1), the first and second enzymes of de novo serine synthetic pathway. Augmented serine synthesis leads to GSH/ROS imbalance and supports pyrimidine biosynthesis, maintaining tumor initiation capacity and enhancing gemcitabine chemoresistance. Mechanistically, we identify that IDH1WT interacts with and stabilizes PHGDH and fragile X-related protein-1 (FXR1) by impeding their association with the E3 ubiquitin ligase parkin by coimmunoprecipitation assay and proximity ligation assay. Subsequently, stabilized FXR1 supports PSAT1 mRNA stability and translation, as determined by actinomycin D chase experiment and in vitro translation assay. Disrupting IDH1WT-PHGDH and IDH1WT-FXR1 interactions synergistically reduces NSCLC stemness and sensitizes NSCLC cells to gemcitabine and serine/glycine-depleted diet therapy in lung cancer xenograft models. Collectively, our findings offer insights into the role of IDH1WT in serine metabolism, highlighting IDH1WT as a potential therapeutic target for eradicating TICs and overcoming gemcitabine chemoresistance in NSCLC.

Development and validation of a nomogram based on preoperative variables for predicting recurrence-free survival in stage IA lung adenocarcinoma.

BACKGROUND: This study aimed to establish a nomogram for predicting risk of recurrence and provide a model for decision-making between lobectomy and sublobar resection in patients with stage IA lung adenocarcinoma. METHODS: Patients diagnosed with stage IA lung adenocarcinoma (LUAD) between December 2010 and October 2018 from Cancer Hospital Chinese Academy of Medical Sciences were included. Patients were randomly assigned to training and validation cohorts, accounting for 70% and 30% of the total cases, respectively. We collected laboratory variables before surgery. Univariate and multivariate analyses were performed in the training cohort to identify variables significantly associated with recurrence-free survival (RFS) which were subsequently used to construct a nomogram. Validation was conducted in both cohorts. A receiver operating characteristic curve was used to determine the optional cutoff values of the scores calculated from the nomogram. Patients were then divided into low- and high-risk groups. Survival was performed to determine if the nomogram could guide the operation method. RESULTS: A total of 543 patients were included in this study. Gender, albumin level, carcinoembryonic antigen level and cytokeratin-19-fragment level were included in the nomogram. In both cohorts, the nomogram stratified the patients into high- and low-risk groups in terms of RFS. In particular, there was a significant difference in RFS between lobectomy and sublobar resection in the high-risk group. CONCLUSIONS: Gender, albumin level, carcinoembryonic antigen level and cytokeratin-19-fragment level are valuable markers in predicting recurrence and can guide surgical practice in patients with stage IA LUAD.

Racial disparities in histological subtype, stage, tumor grade and cancer-specific survival in lung cancer.

Background: Racial differences in lung cancer survival are well documented in the United States, but the fundamental causes are less clear. In this study we aimed to examine racial differences in lung cancer-specific survival (LCSS) and explore mediating factors. Methods: We used the Surveillance, Epidemiology and End Results database to obtain data pertaining to lung cancer patients from 2004 to 2017. Outcome was LCSS and covariates included nonclinical (age at diagnosis, gender, marital status, race) and clinical factors (tumor site, year of diagnosis, tumor grading, histological subtype, tumor-node-metastasis (TNM) stage, surgery status, chemotherapy status and radiation status). Kaplan-Meier methods served for comparative LCSS disparities among patients of different racial origins. Meanwhile, univariate and multivariate survival analyses were performed to determine racial disparities in LCSS. Results: Among 61,961 lung cancer patients, 75.70% were White, 12.80% were Black, 11.30% were Asian or Pacific Islander (API), and 0.20% were American Indian/Alaska Native (AIAN). In API patients, adenocarcinoma patients (54.5%) were more frequent than in White patients (43.2%), Black patients (44.1%) and American Indian/Alaska Native patients (41.2%). Black and API patients exhibited higher stage than White patients (P<0.01). However, our multivariate analysis identified API patients exhibited better LCSS than White patients (HR: 0.90, 95% CI: 0.88-0.93). Kaplan-Meier survival analysis confirmed that API patients exhibited best LCSS, especially in stage IV adenocarcinoma. Conclusions: The novel evidence obtained from this study enrich our knowledge of racial differences among lung cancer patients and suggest that race may be associated with LCSS.