bims-meluca 2024-08-25 papers

Front Oncol. 2024 ;14 1357583

TP53 co-mutations in advanced lung adenocarcinoma: comparative bioinformatic analyses suggest ambivalent character on overall survival alongside KRAS, STK11 and KEAP1 mutations.

Armin Frille, Myriam Boeschen, Hubert Wirtz, Mathias Stiller, Hendrik Bläker, Maximilian von Laffert.

Background: Recently, we could show that the co-mutations of KRAS + KEAP1, STK11 + KEAP1 and KRAS + STK11 + KEAP1 lead to a significantly shorter median overall survival (mOS) across treatments by analyzing multiple datasets. TP53, a tumor suppressor gene, plays a crucial role in regulating cell cycle progression. Its mutations occur in approximately 40-50% of non-small lung cancer (NSCLC). Co-occurrence of all four mentioned mutations has been a matter of debate for years. The aim of this study was to assess the distribution of these four mutations and the influence of the different co-mutational patterns on survival.
Methods: We present a comparative bioinformatic analysis and refer to data of 4,109 patients with lung adenocarcinoma (LUAD).
Results: Most of the mutations within the LUAD belong to TP53-only (29.0%), quadruple-negative (25.9%) and KRAS-only (13.4%). Whereas TP53-mutations seem to have protective effects in the context of further KEAP1- and KRAS + KEAP1-alterations (improved mOS), their role seems contrary if acquired in an already existing combination of mutations as KRAS + STK11, KRAS + STK11 + KEAP1 and STK1 + KEAP1. TP53 co-mutationshad a negative influence on KRAS-only mutated LUAD (mOS reduced significantly by more than 30%).
Discussion: These data underline the need for complex mutational testing to estimate prognosis more accurately in patients with advanced LUAD.

Keywords: KEAP1; KRAS; NSCLC; STK11; TP53; co-mutations; lung adenocarcinoma; survival

DOI: https://doi.org/10.3389/fonc.2024.1357583

J Proteome Res. 2024 Aug 20.

Metabolomic Profiling of Tumor Tissues Unveils Metabolic Shifts in Non-Small Cell Lung Cancer Patients with Concurrent Diabetes Mellitus.

Xiaohong Lyu, Yujue Wang, Yuan Xu, Zhewei Zhao, Hongsheng Liu, Zeping Hu.

A comprehensive understanding of the exact influence of type 2 diabetes mellitus (T2DM) on the metabolic status of non-small cell lung cancer (NSCLC) is still lacking. This study explores metabolic alterations in tumor tissues among patients with coexisting NSCLC and T2DM in comparison with NSCLC patients. A combined approach of clinical analysis and metabolomics was employed, including 20 NSCLC patients and 20 NSCLC+T2DM patients. Targeted metabolomics analysis was performed on tumor tissues using the liquid chromatography-mass spectrometry (LC-MS) approach. A clear segregation was observed between NSCLC+T2DM and matched NSCLC tissue samples in Orthogonal Partial Least Squares Discrimination Analysis (OPLS-DA). Furthermore, the levels of 7 metabolites are found to be significantly different between diabetes/nondiabetes tumor tissue samples. The related pathways included arginine biosynthesis, glutathione metabolism, arginine and proline metabolism, purine metabolism, biotin metabolism, and histidine metabolism. 3-Phenyllactic acid, carnitine-C5, carnitine-C12, and serotonin showed a positive linear correlation with fasting blood glucose levels in NSCLC patients. Uridine, pipecolic acid, cytosine, and fasting blood glucose levels were found to have a negative correlation. Our results suggest that NSCLC patients with concurrent T2DM exhibit distinct metabolic shifts in tumor tissues compared to those of solely NSCLC patients.

Keywords: diabetes; metabolites; metabolomics; non-small cell lung cancer

DOI: https://doi.org/10.1021/acs.jproteome.3c00924

Chin Med J Pulm Crit Care Med. 2023 Jun;1(2): 119-124

Low BMI patients with advanced EGFR mutation-positive NSCLC can get a better outcome from metformin plus EGFR-TKI as first-line therapy: A secondary analysis of a phase 2 randomized clinical trial.

Rui Han, Jianghua Li, Yubo Wang, Tingting He, Jie Zheng, Yong He.

Background: The synergistic association between metformin and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) has been confirmed in in vitro studies. It is still controversial which patients can benefit from metformin plus EGFR-TKIs treatment. Body mass index (BMI) was proved to be independently associated with prolonged progression-free survival (PFS) and overall survival (OS). This study aimed to investigate whether BMI is associated with the synergistic effect of metformin and EGFR-TKIs in advanced EGFR mutation (EGFRm)-positive non-small cell lung cancer (NSCLC) among nondiabetic Asian population.
Methods: We performed a post hoc analysis of a prospective, double-blind phase II randomized clinical trial (COAST, NCT01864681), which enrolled 224 patients without diabetes with treatment-naïve stage IIIB-IV EGFRm NSCLC. We stratified patients into those with a high BMI (≥24 kg/m2) and those with a low BMI (<24 kg/m2) to allow an analysis of the difference in PFS and OS between the two groups. The PFS and OS were analyzed using Kaplan-Meier curves, and the differences between groups were compared using log-rank test.
Results: In the univariate analysis, patients who had a high BMI (n = 56) in the gefitinib + metformin group (n = 28) did not have a better PFS (8.84 months vs. 11.67 months; P = 0.351) or OS (15.58 months vs. 24.36 months; P = 0.095) than those in the gefitinib + placebo group (n = 28). Similar results were also observed in the low-BMI groups. Strikingly, in the metformin plus gefitinib group, patients who had low BMI (n = 69) showed significantly better OS than those with high BMI (24.89 months [95% CI, 20.68 months-not reached] vs. 15.58 months [95% CI, 13.78-31.53 months]; P = 0.007), but this difference was not observed in PFS (10.78 months vs. 8.84 months; P = 0.285).
Conclusions: Our study showed that nondiabetic Asian advanced NSCLC patients with EGFR mutations who have low BMI seem to get better OS from metformin plus EGFR-TKI treatment.

Keywords: Body mass index; Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs); Gefitinib; Metformin; Non-small cell lung cancer

DOI: https://doi.org/10.1016/j.pccm.2023.04.006

PLoS One. 2024 ;19(8): e0309394

Neutralizing antibody against GDF15 for treatment of cancer-associated cachexia.

Junyi Xiong, Guojin Wu, Jinying Ning, Junlin Yan, Jian Yang, Jinsen Kang.

GDF15 (growth differentiation factor 15), also known as macrophage inhibitory cytokine 1 (MIC-1), is a circulating protein involved in the regulation of energy balance and weight control. Elevated levels of GDF15 have been associated with cachexia and reduced survival rates in cancer patients. Through the activation of the GFRAL (GDNF-family receptor α-like)-RET (Rearranged during Transfection) signaling pathway, GDF15 can induce weight loss, making it a potential target for treating cachexia. Currently, there are no approved antibody drugs specifically targeting GDF15 for cancer cachexia treatment. However, efforts have been made to develop antibody-based therapeutics against this emerging target. In this study, we generated a monoclonal antibody KY-NAb-GDF15 against GDF15 that effectively blocks downstream signaling mediated by GFRAL upon stimulation by GDF15. This antibody demonstrates robust neutralizing activity and exhibits high binding specificity. Importantly, our findings indicate that this antibody holds promise in alleviating cancer-induced cachexia and mitigating chemotherapy-induced weight loss, thereby offering significant therapeutic potential for managing cancer cachexia.

DOI: https://doi.org/10.1371/journal.pone.0309394