bims-meluca Biomed News
on Metabolism of non-small cell lung carcinoma
Issue of 2021‒04‒11
two papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge
  1. AMPK activation by ASP4132 inhibits non-small cell lung cancer cell growth.
  2. Role of combining neutrophil-to-lymphocyte ratio and pretreatment body mass index in predicting progression-free survival in patients with non-small cell lung cancer treated with nivolumab.
  1. Cell Death Dis. 2021 Apr 06. 12(4): 365
    AMPK activation by ASP4132 inhibits non-small cell lung cancer cell growth.
    Xia YC, Zha JH, Sang YH, Yin H, Xu GQ, Zhen J, Zhang Y, Yu BT.
      Activation of adenosine monophosphate-activated protein kinase (AMPK) is able to produce significant anti-non-small cell lung cancer (NSCLC) cell activity. ASP4132 is an orally active and highly effective AMPK activator. The current study tested its activity against NSCLC cells. In primary NSCLC cells and established cell lines (A549 and NCI-H1944) ASP4132 potently inhibited cell growth, proliferation and cell cycle progression as well as cell migration and invasion. Robust apoptosis activation was detected in ASP4132-treated NSCLC cells. Furthermore, ASP4132 treatment in NSCLC cells induced programmed necrosis, causing mitochondrial p53-cyclophilin D (CyPD)-adenine nucleotide translocase 1 (ANT1) association, mitochondrial depolarization and medium lactate dehydrogenase release. In NSCLC cells ASP4132 activated AMPK signaling, induced AMPKα1-ACC phosphorylation and increased AMPK activity. Furthermore, AMPK downstream events, including mTORC1 inhibition, receptor tyrosine kinases (PDGFRα and EGFR) degradation, Akt inhibition and autophagy induction, were detected in ASP4132-treated NSCLC cells. Importantly, AMPK inactivation by AMPKα1 shRNA, knockout (using CRISPR/Cas9 strategy) or dominant negative mutation (T172A) almost reversed ASP4132-induced anti-NSCLC cell activity. Conversely, a constitutively active AMPKα1 (T172D) mimicked and abolished ASP4132-induced actions in NSCLC cells. In vivo, oral administration of a single dose of ASP4132 largely inhibited NSCLC xenograft growth in SCID mice. AMPK activation, mTORC1 inhibition and EGFR-PDGFRα degradation as well as Akt inhibition and autophagy induction were detected in ASP4132-treated NSCLC xenograft tumor tissues. Together, activation of AMPK by ASP4132 potently inhibits NSCLC cell growth in vitro and in vivo.
    DOI:  https://doi.org/10.1038/s41419-021-03655-2
  2. Exp Ther Med. 2021 May;21(5): 526
    Role of combining neutrophil-to-lymphocyte ratio and pretreatment body mass index in predicting progression-free survival in patients with non-small cell lung cancer treated with nivolumab.
    Dragomir R, Dragomir AS, Negru A, Săftescu S, Popovici D, Schenker M, Lupușoru R, Negru Ș.
      Identifying markers capable of predicting outcomes in lung cancer patients treated with nivolumab represents a growing research interest. The combination of neutrophil-to-lymphocyte ratio (NLR) and body mass index (BMI) may help predict treatment efficacy. Thus, the present study aimed to investigate the influence of NLR and BMI on progression-free survival (PFS) in non-small-cell lung cancer (NSCLC) patients treated with nivolumab. A retrospective study was made on 80 patients with NSCLC that were treated with nivolumab at the OncoHelp Oncology Center, Timisoara, Romania after platinum-based chemotherapy, from January 2018 to April 2020. Patients were administered nivolumab at a dose of 3 mg/m2 or 240 mg total dose, every 2 weeks. The predictive impact of NLR (baseline at 2 and 4 weeks after the start of nivolumab) and BMI for disease progression was assessed. Median PFS for subjects with NLR <3 before treatment was 18.5 weeks, while in subjects with NLR ≥3 was 14 weeks (P=0.50). Median PFS for subjects with NLR2 <3 at 2 weeks after treatment was 21 weeks, while in subjects with NLR2 ≥3, PFS was 14 weeks (P=0.17). Median PFS for subjects with NLR4 <3 at 4 weeks after treatment was 23 weeks, while in subjects with NLR4 ≥3, PFS was 19 weeks (P=0.33). Multivariate analysis for the association with PFS showed that baseline NLR, male sex and BMI were associated independently, thus we could develop a significant statistical model [AUROC=0.76, 95% CI (0.45-0.89), P=0.03], a new predictive score for PFS. The assessment of NLR and BMI may represent simple and useful biomarkers; combining them and taking into consideration the male sex may predict PFS in patients with advanced NSCLC treated with nivolumab.
    Keywords:  NSCLC; body mass index; neutrophil-to-lymphocyte ratio; nivolumab; non-small-cell lung cancer; nutritional status; predictive score; progression-free survival
    DOI:  https://doi.org/10.3892/etm.2021.9958
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