bims-meluca 2025-08-17 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2025–08–17
six papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Targeting Metabolic Vulnerabilities Reveals Hexokinase 2 as a Key Mediator of Resistance to Osimertinib in Non-Small Cell Lung Cancer Models.
Synergistic effects of oncogene inhibition and pyruvate dehydrogenase kinase blockade in resistant NSCLC cells.
Effects of Sarcopenia on the Outcomes and Safety of Chemoradiotherapy Followed by Durvalumab for the Treatment of Patients With Locally Advanced Non-Small Cell Lung Cancer.
IL-6 promotes metastasis and EMT of non-small cell lung cancer cells by up-regulating FGL1 via STAT3 pathway.
Serotonin Metabolism Shapes the Tumor Immune Microenvironment and Serves as a Therapeutic Target in Lung Cancer.
Cachexia index as a biomarker for cancer cachexia and quality of life in patients with gastric cancer.

ACS Pharmacol Transl Sci. 2025 Aug 08. 8(8): 2646-2662

Targeting Metabolic Vulnerabilities Reveals Hexokinase 2 as a Key Mediator of Resistance to Osimertinib in Non-Small Cell Lung Cancer Models.

Yizhen Guo, Ding Huang, Yan Zhou, Maoxin Ran, Shaolin Zhang, Kin Yip Tam.

  Acquired resistance to osimertinib (OSI) poses a significant challenge in the treatment of epidermal growth factor receptor mutant non-small cell lung cancer (NSCLC). Although OSI is effective as a first-line salvage therapy in T790M-positive patients following progression on first- or second-generation EGFR-TKIs (erlotinib, gefitinib, and afatinib), the inevitable development of acquired resistance limits its therapeutic efficacy. This study reveals that OSI-resistant (OSIR) NSCLC cells underwent metabolic reprogramming characterized by enhanced glycolysis and upregulation of hexokinase 2 (HK2). We demonstrated that HK2 inhibitor, benserazide, exhibited significant anticancer effects in OSIR cell models and mediated by reactive oxygen species. Our results suggested that HK2 inhibition effectively modulated the enhanced glycolysis, activated the AMPK-mTOR-autophagy axis, and unexpectedly interfered with NF-κB signaling through direct HK2-IKKβ interaction. Excitingly, the protein expression level and activity of pyruvate dehydrogenase kinase 1 (PDK1) in OSIR cells were upregulated upon HK2 inhibition, indicating a pro-survival role. Combined inhibition of HK2 and PDK1 synergistically inhibited the proliferation of OSIR cells and significantly suppressed tumor growth in an OSIR cell xenograft model, outperforming the single use of HK2 inhibitor. This combination successfully rectified aberrant glucose metabolism and enhanced oxidative phosphorylation. Our findings identified HK2 as a crucial mediator in overcoming OSI resistance and suggested that combined inhibition of HK2 and PDK1 could be a promising approach in OSIR NSCLC.

Keywords:  NF-κB signaling; cancer metabolism; glycolysis reprogramming; hexokinase 2; non-small cell lung cancer; osimertinib resistance

DOI:  https://doi.org/10.1021/acsptsci.5c00235
Biochim Biophys Acta Mol Basis Dis. 2025 Aug 08. pii: S0925-4439(25)00362-X. [Epub ahead of print]1871(8): 168014

Synergistic effects of oncogene inhibition and pyruvate dehydrogenase kinase blockade in resistant NSCLC cells.

Luisa Amato, Caterina De Rosa, Daniela Omodei, Camilla C Tufano, Rossella Buono, Concetta Tuccillo, Giovanni N Roviello, Michele Spinelli, Carolina Fontanarosa, Federica Papaccio, Rosa Camerlingo, Floriana Morgillo, Andrea Carpentieri, Angela Amoresano, Virginia Tirino, Francesca Iommelli, Carminia Maria Della Corte, Silvana Del Vecchio, Viviana De Rosa.

  The metabolic reprogramming of tumor cells plays a critical role in cancer progression, contributing to drug resistance and tumor survival. Tyrosine kinase inhibitors (TKIs) have shown promising clinical results by targeting specific signaling pathways in cancer cell proliferation, survival, and metastasis and are now standard of care for NSCLC with actionable mutations. However, secondary resistance to TKIs remains a significant challenge. Here, we explored the rationale behind combining TKIs with an inhibitor of glucose metabolism (dichloroacetate, DCA), focusing on the synergistic effects from dual inhibition of oncogenic and metabolic reprogramming. We selected three NSCLC cell line models (H1975, H1993, A549) with EGFR/MET/KRAS mutations and determined the optimal DCA dose (500 μM) to reverse the Warburg effect. TKIs in combination with DCA (CI < 1, indicating synergy) altered cell metabolism, by improving oxidative phosphorylation via reduced glucose consumption (~50 %, p < 0.05) and increased ATP (~50 %, p < 0.0001), particularly mitoATP, confirmed by metabolite levels. The combination also reduced cell proliferation (S phase p < 0.001), increased cell death (~40 %, p < 0.0001 less MMP, ~1.6 fold more BIM, 2.5-fold more autophagy) and blocked invasion (~3 fold fewer protrusions). Our findings show DCA potentiates TKIs at lower doses, likely via Warburg effect reversal. These changes in tumor behaviour leads to a higher pro-apoptotic status responsible for an increased tumor response and, in parallel, the lower doses reduced alternative evasion pathways contributing to decrease of tumor invasion and resistance mechanism. This study shed light on a new potential combined therapeutic approach to improve clinical outcomes in targeted cancer therapy scenarios.

Keywords:  Cell death; Combined therapy; Oncogene addiction; PDKs

DOI:  https://doi.org/10.1016/j.bbadis.2025.168014
Thorac Cancer. 2025 Aug;16(16): e70145

Effects of Sarcopenia on the Outcomes and Safety of Chemoradiotherapy Followed by Durvalumab for the Treatment of Patients With Locally Advanced Non-Small Cell Lung Cancer.

Kentaro Tamura, Hidehito Horinouchi, Mototaka Miyake, Ken Masuda, Yuki Shinno, Yusuke Okuma, Tatsuya Yoshida, Noboru Yamamoto, Yasushi Goto.

   BACKGROUND: Sarcopenia is associated with poor outcomes of various cancers treated with immune checkpoint inhibitors. Durvalumab is the standard of care for patients with locally advanced (LA) non-small cell lung cancer (NSCLC) after chemoradiation therapy (CRT). However, the effect of sarcopenia on the efficacy and safety of durvalumab in patients with LA-NSCLC remains unclear.
METHODS: This single-center retrospective study was conducted between 2018 and 2021. Body composition indices were measured using computed tomography scans taken at the third lumbar vertebra before and after CRT. The cutoff values were set based on the change ratios for each index before and after CRT. Tumor response, survival, and the efficacy and safety of durvalumab were compared between patients who showed skeletal muscle loss and those who did not.
RESULTS: Among 153 eligible patients (median age: 65 years; 74.5% men), skeletal muscle index (SMI) significantly decreased during CRT. With the threshold set at a -10% change in SMI, no significant difference in objective response rate (ΔSMI ≤ -10% vs. ΔSMI > -10%: 76.6% vs. 75.7%, p = 1.000), progression-free survival (hazard ratio [HR], 0.99, p = 0.983), overall survival (HR 1.04, p = 0.909), or the frequency of immune-related adverse events (44.9% vs. 44.2%, p = 1.000) was observed between the two groups.
CONCLUSIONS: Although muscle loss during CRT is common, it does not compromise the efficacy or safety of subsequent durvalumab therapy in patients with LA-NSCLC. Future studies are needed to delineate sarcopenia criteria specific to LA-NSCLC and assess interventions, including rehabilitation and pharmacotherapy.

Keywords:  chemoradiation therapy; durvalumab; locally‐advanced non‐small cell lung cancer; sarcopenia

DOI:  https://doi.org/10.1111/1759-7714.70145
Transl Cancer Res. 2025 Jul 30. 14(7): 3973-3990

IL-6 promotes metastasis and EMT of non-small cell lung cancer cells by up-regulating FGL1 via STAT3 pathway.

Jing Liu, Qiuge Liu, Wenjing Qian, Chengguo Zong, Ruoyu Wang.

   Background: It has been reported that IL-6 induces the synthesis and secretion of fibrinogen-like protein 1 (FGL1) in liver cells as well as promotes the regeneration of liver cells. FGL1 is upregulated in human cancers, especially in non-small cell lung cancer (NSCLC). FGL1 is involved in the regulation of epithelial-mesenchymal transition (EMT) in gastric cancer (GC) cells. However, the role of IL-6/FGL1 signaling axis in the EMT process of NSCLC cells and its mechanism remain unclear. In this study, we investigated the role of FGL1 in mediating the metastasis and EMT processes of NSCLC cells, as well as the underlying signaling mechanisms.
Methods: The Cancer Genome Atlas (TCGA) database and STARBASE database were used to analyze the biological information of FGL1 gene expression in NSCLC patients, and the database information was verified by clinical data. Transwell, Western blotting and microscopy were used to observe the effects of FGL1 on the metastasis and proliferation of NSCLC cells and the occurrence of EMT and its potential signaling pathway proteins.
Results: Database analysis and clinical data showed that the prognosis of NSCLC patients with high FGL1 expression was poor. Cell phenotypic experiments showed that FGL1 silencing significantly reduced proliferation, migration and EMT of NSCLC cells, suggesting that the expression level of FGL1 may be significantly correlated with migration ability and EMT in lung cancer cells. In addition, the FGL1-neutralizing antibody inhibited EMT and metastasis of NSCLC cells in vivo. Further studies showed that IL-6 may mediate EMT by inducing FGL1 expression through the STAT3 pathway in lung cancer cells. Furthermore, treatment with a STAT3 inhibitor significantly inhibited the IL-6-induced FGL1 expression and EMT in NSCLC cells.
Conclusions: IL-6 regulates FGL1 expression to mediate metastasis and EMT of NSCLC cells through the STAT3 signaling pathway.

Keywords:  IL-6/STAT3; Non-small cell lung cancer (NSCLC); epithelial-mesenchymal transition (EMT); fibrinogen-like protein 1 (FGL1); metastasis

DOI:  https://doi.org/10.21037/tcr-2025-119
Anticancer Agents Med Chem. 2025 Aug 08.

Serotonin Metabolism Shapes the Tumor Immune Microenvironment and Serves as a Therapeutic Target in Lung Cancer.

Miersalijiang Yasen, Naikun Sun, Jiude Jia, Weixiang Hong, Leiting Zhuang, Jinwang Huang, Xiaohui Chen, Wenhui Shen.

   INTRODUCTION: Lung cancer progression involves complex interactions between metabolic pathways and the immune microenvironment. The role of serotonin, a tryptophan-derived metabolite, in immune responses to lung tumors remains unclear.
METHODS: An orthotopic lung cancer model was established by intravenously injecting KP (KrasG12D/p53-/-) cells into C57BL/6 mice. Metabolomic and flux analyses were conducted on tumor versus normal lung tissues. Serotonin was administered to tumor-bearing mice, followed by immunofluorescence and flow cytometry to assess immune responses. Human lung cancer datasets were analyzed to validate clinical relevance.
RESULTS: Tumor tissues exhibited a significant decrease in serotonin levels. Although tryptophan, serotonin, and kynurenine levels were decreased overall, flux analysis revealed a metabolic shift favoring kynurenine synthesis, with a ~10-fold increase in the kynurenine-to-serotonin ratio. Serotonin supplementation significantly prolonged survival and enhanced dendritic cell and CD8⁺ T cell infiltration and activation in tumors. Analysis of public datasets showed that serotonin expression positively correlated with CD8⁺ T cell activation signatures and patient prognosis.
DISCUSSION: By revealing serotonin as a potential biomarker and therapeutic target, this study paves new avenues for improving lung cancer treatment strategies through modulation of the immune microenvironment. Moreover, the precise receptor-mediated mechanisms underlying serotonin's immunomodulatory effects remain to be clarified, and translational validation in human tissues is warranted to strengthen clinical relevance.
CONCLUSION: Serotonin deficiency in the tumor microenvironment of the lung suppresses antitumor immunity. Its restoration reverses immune dysfunction and limits tumor progression. These findings identify serotonin as a potential metabolic regulator and immunotherapeutic target in lung cancer.

Keywords:  Serotonin; immune microenvironment; immunofluorescence.; lung cancer; metabolomic

DOI:  https://doi.org/10.2174/0118715206408134250801050919
BMC Cancer. 2025 Aug 09. 25(1): 1293

Cachexia index as a biomarker for cancer cachexia and quality of life in patients with gastric cancer.

Yan Huang, Zhenhua Huang, Wenji Hou, Chen Wang, Xiuhua Wang, Junbo Zuo.

   BACKGROUND: Cachexia is associated with adverse clinical outcomes in patients with gastric cancer (GC); therefore, a convenient and reliable method for monitoring cachexia is essential. This study aimed to evaluate the utility of the cachexia index (CXI) as a biomarker for estimating cancer cachexia and health-related quality of life (HRQoL) in GC patients.
METHODS: The CXI was calculated as the skeletal muscle index (SMI) × serum albumin / neutrophil-lymphocyte ratio (NLR). Diagnosis of cachexia was based on Asian Working Group for Cachexia (AWGC) criteria and Fearon's criteria. Univariate and multivariate logistic regression analyses were carried out to identify potential risk factors related to cancer cachexia and HRQoL respectively. Receiver Operating Characteristics (ROC) analysis was conducted to evaluate the diagnostic value in identifying cancer cachexia, and the area under the ROC curve (AUC) was calculated.
RESULTS: This study comprised a total of 431 patients diagnosed with GC, including 309 males (71.7%) and 122 females (28.3%), with a median age of 68 years. Compared to patients without cachexia, the CXI values were significantly lower in those with cachexia defined by either the AWGC criteria or Fearon's criteria (p < 0.001). After adjusting for potential confounding factors in the multivariate logistic analysis, CXI was found to be independently associated with AWGC-defined cachexia (OR = 0.98, 95% CI: 0.97-0.99, p < 0.001), but not with Fearon-defined cachexia (OR = 1.00, 95% CI: 0.99-1.01, p = 0.601). Based on ROC curve analysis, the AUC was 0.752 for males and 0.717 for females, with cut-off CXI values of 74.46 and 43.80 for identifying AWGC-defined cachexia, respectively. Patients with low CXI demonstrated greater severity in major aspects of HRQoL, and low CXI was independently associated with poor HRQoL (OR = 1.79, 95% CI = 1.05-3.07, p = 0.033).
CONCLUSIONS: CXI could serve as a useful biomarker for evaluating cancer cachexia and HRQoL in patients with GC.

Keywords:  Cachexia index; Cancer cachexia; Gastric cancer; Quality of life

DOI:  https://doi.org/10.1186/s12885-025-14752-2