bims-meluca 2026-01-25 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2026–01–25
eight papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

KEAP1 mutations activate the NRF2 pathway to drive cell growth and migration, and attenuate drug response in thyroid cancer.
Predictive value of circulating microRNA-21 levels in patients with advanced non-small cell lung cancer treated with immunotherapy.
IL-6 drives chemoimmunotherapy resistance in NSCLC by reprogramming myeloid cells and impairing cytotoxic lymphocyte function.
NF-κB activation as a pro-survival signal from pharmacological inhibition of pyruvate dehydrogenase kinase 1 in non-small-cell lung carcinoma cell models.
Evaluation of ICAM and VCAM as biomarkers in serum and bronchoscopic lavage samples of lung cancer patients.
Novel 5,7-Diazaindole-based ERK5 inhibitor induces endoplasmic reticulum stress and mitochondrial apoptosis in non-small cell lung Cancer.
Inhibition of GALNT7 suppresses cell proliferation and invasiveness while elevating cell apoptosis via the inactivation of the AKT pathway in non-small cell lung cancer.
GDF15 in the tumor microenvironment: A central mediator of cancer immunometabolism and therapeutic resistance.

Front Oncol. 2025 ;15 1685379

KEAP1 mutations activate the NRF2 pathway to drive cell growth and migration, and attenuate drug response in thyroid cancer.

Nicholas E Bambach, Julio C Ricarte-Filho, Erin R Reichenberger, Christian Hernandez-Padilla, Kyle Hinkle, Amber Isaza, Andrew J Bauer, Aime T Franco.

  The KEAP1/NRF2 pathway, a major regulator of the cellular oxidative stress response, is frequently activated in human cancers. Often mediated by loss-of-function mutations in KEAP1, this activation causes increased NRF2 transcriptional activity and constitutive activation of the antioxidant response. While KEAP1 mutations have been well documented in various cancers, their presence and role in thyroid carcinoma have remained largely unexplored. In this study, we sequenced pediatric thyroid tumors and analyzed publicly available datasets, identifying 81 KEAP1 mutations in tumors across a range of histologies. In these tumors, we further identified frequent biallelic loss of KEAP1 via 19p13.2 loss of heterozygosity (LOH). MAPK-activating alterations were found in a subset of KEAP1-mutant cases, but they were mutually exclusive with 19p13.2 LOH. Transcriptome analysis also revealed significant activation of the NRF2 pathway in KEAP1-mutant tumors. Four additional cases with similar transcriptional profiles but lacking mutational data were identified, likely representing putative KEAP1 mutants. Using in vitro cell line models, we then profiled the functional consequences of KEAP1 knockout in cells with and without known driver alterations. In these models, we show that KEAP1 loss leads to an NRF2-dependent upregulation of AKR1C3, GCLC, NQO1, and TXNRD1, along with increased proliferation and migration irrespective of MAPK mutational status. We also demonstrate that loss of KEAP1 reduces sensitivity of RET fusion-positive cells to selpercatinib, consistent with previous reports that these alterations promote drug resistance in other malignancies. In this study, we comprehensively profile KEAP1 mutations in thyroid tumors, showing that they are more prevalent and functionally significant than previously recognized. These findings position KEAP1 mutations as novel oncogenic variants in thyroid cancer and support the integration of KEAP1/NRF2 pathway profiling into future studies and clinical frameworks.

Keywords:  KEAP1; LOH; NRF2; chr19p; mutation; pediatric; selpercatinib; thyroid cancer

DOI:  https://doi.org/10.3389/fonc.2025.1685379
Ecancermedicalscience. 2025 ;19 1989

Predictive value of circulating microRNA-21 levels in patients with advanced non-small cell lung cancer treated with immunotherapy.

Cong Wang, Shan Jiang, Junfang Bi, Xu Xu.

   Background: Pembrolizumab has been widely used to curb the disease progression of non-small-cell lung cancer (NSCLC), but 20% of patients treated with pembrolizumab have disease progression. MicroRNA-21 (miRNA-21) was highly expressed in NSCLC and promoted the occurrence of malignancy-related processes. However, the predictive value of miR-21 in NSCLC patients who underwent immunotherapy remains unknown. We aim to investigate the predictive role of miR-21 in NSCLC patients who received pembrolizumab-based combination therapy.
Methods: We included 136 advanced NSCLC patients and miR-21 levels were identified. The combined positive score (CPS) was calculated and CPS≥1 was considered PD-L1 positive tumour cells in patients with NSCLC. Circulating miR-21 expressions between responders and non-responders were analysed. The overall survival (OS) and progression-free survival (PFS) according to miR-21 status were also investigated.
Results: Patients categorised as responders had significantly lower expression of miRNA-21 (p < 0.001). Notably, miR-21 levels were also lower in patients with CPS≥1 (p < 0.001). According to the 50th percentile of miR-21 concentrations, patients with lower miR-21 levels had significantly improved OS (69.6 (95% CI: 63.8-75.4) versus 14.4 (95% CI: 9.9-18.9), p<0.001) and PFS than those with higher miR-21 levels (64.2 (95% CI: 58-70.4) versus 17.0 (95% CI: 16.5-17.5), p<0.001).
Conclusion: MiR-21 levels were significantly correlated with the therapeutic effect and prognosis of NSCLC patients who received immunotherapy. MiR-21 holds promise as a potential biomarker of response to immunotherapy in NSCLC and it may suggest that miR-21 could be regarded as a novel indicator for prognostic prediction in NSCLC patients.

Keywords:  biomarker; microRNA-21; molecular diagnostics; non-small-cell lung cancer; therapeutic effect

DOI:  https://doi.org/10.3332/ecancer.2025.1989
Cancer Lett. 2026 Jan 17. pii: S0304-3835(26)00022-4. [Epub ahead of print] 218259

IL-6 drives chemoimmunotherapy resistance in NSCLC by reprogramming myeloid cells and impairing cytotoxic lymphocyte function.

Yaning Yang, Chengming Liu, Lu Yang, Sufei Zheng, Haiyan Xu, Shuyang Zhang, Linyan Tian, Nan Sun, Jie He, Yan Wang.

  Primary resistance to first-line chemoimmunotherapy remains a significant challenge in treating advanced non-small cell lung cancer (NSCLC). Although cytokines such as interleukin-6 (IL-6) have been implicated in resistance to immune checkpoint inhibitor (ICI) monotherapy, their predictive value for chemoimmunotherapy outcomes and the underlying mechanisms are less defined. This study investigated the prognostic significance of the baseline plasma IL-6 levels and the role of this cytokine in shaping the tumour immune microenvironment (TIME) of NSCLC. Here, We retrospectively analysed data on 123 advanced NSCLC patients treated with anti-PD-1 inhibitors plus chemotherapy. Baseline plasma IL-6 levels were measured via ELISA. Progression-free survival (PFS) and overall survival (OS) were assessed via Kaplan-Meier and Cox regression analyses. We established murine lung adenocarcinoma (LLC) and squamous cell carcinoma (KLN205) models with IL-6 overexpression (IL6a) or inhibition (IL6i) and treated them with anti-PD-1 therapy ± chemotherapy. Tumour growth was monitored, and single-cell RNA sequencing (scRNA-seq) was performed on tumour-infiltrating immune cells. The results showed that patients with high baseline plasma IL-6 levels (>7.002 pg/mL) exhibited significantly worse PFS (median: 7.20 vs. 16.63 months, P=0.001) and OS (median: 15.63 vs. 32.80 months, P=0.001) than those with low baseline levels. A high IL-6 level was an independent predictor of worse PFS (HR=2.42, P<0.001) and OS (HR=2.96, P<0.001) and was correlated with progressive disease (PD, P=0.018). In murine models, IL-6 overexpression diminished the antitumour efficacy of anti-PD-1 therapy combined with chemotherapy. Moreover, scRNA-seq analysis revealed that IL-6 overexpression skewed macrophage polarisation toward immunosuppressive phenotypes (characterised by Hilpda and Nr4a1 expression) and reduced the proportion of cytotoxic CD8+ T-cells while increasing the proportion of regulatory T-cells (Tregs). Conversely, IL-6 inhibition promoted an immunostimulatory macrophage phenotype (characterised by increased Ccl8 expression) and enhanced CD8+ T-cell infiltration and function. A high IL-6 level was also correlated with impairment of NK cell degranulation pathways. These findings uncovered that an elevated baseline plasma IL-6 level is a robust independent predictor of primary resistance and poor survival in advanced NSCLC patients receiving first-line chemoimmunotherapy. Mechanistically, IL-6 drives formation of an immunosuppressive TIME by promoting protumour macrophage polarisation. This, in turn, suppress cytotoxic T cell infiltration, promoting Treg expansion, and impairing NK cell function, indicating that the targeting of IL-6 represents a promising strategy to overcome resistance to chemoimmunotherapy.

Keywords:  IL-6; chemoimmunotherapy; immunosuppressive tumor microenvironment; non-small cell lung cancer; resistance

DOI:  https://doi.org/10.1016/j.canlet.2026.218259
Transl Oncol. 2026 Jan 21. pii: S1936-5233(26)00018-5. [Epub ahead of print]65 102681

NF-κB activation as a pro-survival signal from pharmacological inhibition of pyruvate dehydrogenase kinase 1 in non-small-cell lung carcinoma cell models.

Quan Liu, Maoxin Ran, Wenying Shan, Shao-Lin Zhang, Kin Yip Tam.

  Targeting Pyruvate dehydrogenase kinase (PDK) has emerged as one of the potential therapeutic strategies for non-small cell lung carcinoma (NSCLC). 64, a recently reported PDK1 inhibitor derived from 2,2-dichloroacetophenone (DAP), exhibited promising anticancer effects in NSCLC models. Herein, we sought to investigate the mechanism of action of 64 in two NSCLC cell lines, namely, NCI-H1975 and NCI-H1650. We found that 64 induced intrinsic cancer cell apoptosis by releasing cytochrome C (CytC) from mitochondria, leading to caspase-3 and poly (ADP-ribose) polymerase (PARP) cleavage, which was mediated by reactive oxygen species (ROS). Moreover, we have shown that 64 induced mitochondrial membrane potential (MMP) depolarization and AMPK/MAPK activations were also ROS driven. With the aid of sequencing studies and follow-up biochemical evaluations, we found that 64 activated the NF-κB pathway through P38 MAPK, while the combination of P38 MAPK inhibitor SB203580 with 64 diminished such activation. Interestingly, the combined use of 64 and NF-κB inhibitor (JSH-23) increased pro-apoptosis protein (Bax) expression and decreased pro-survival protein (Bcl-2) expression, resulting in enhanced cancer cell apoptosis via JNK pathway. Our results suggested that 64 induces cancer cell apoptosis in NSCLC models through ROS, while NF-κB activation serves as a survival mechanism upon PDK1 inhibition.

Keywords:  Apoptosis; NF-κB; NSCLC; PDK1; ROS

DOI:  https://doi.org/10.1016/j.tranon.2026.102681
Clin Transl Oncol. 2026 Jan 20.

Evaluation of ICAM and VCAM as biomarkers in serum and bronchoscopic lavage samples of lung cancer patients.

Burcu Nur Gülbahar, Alperen Aksakal, Buğra Kerget, Nurinnisa Öztürk, Ömer Araz, Elif Yılmazel Uçar, Leyla Sağlam.

   BACKGROUND: This study aimed to assess the diagnostic and prognostic potential of adhesion molecules ICAM-1, ICAM-2, and VCAM-1 by analyzing their levels in serum and bronchoalveolar lavage (BAL) samples from patients with lung cancer.
METHODS: This prospective, single-center, cross-sectional study was conducted at the chest diseases clinic of Atatürk University Faculty of Medicine from March 2024 to May 2025. Patients diagnosed with malignant or benign lung disease by bronchoscopy, along with a control group of healthy volunteers, were included in the study. Serum samples were collected from all participants, and BAL samples were obtained from the patient groups. ICAM-1, ICAM-2, and VCAM-1 levels were measured by ELISA. Statistical analyses were performed using the SPSS 20.0 software package. Diagnostic accuracy was evaluated with ROC analysis, and 1-year survival was assessed using Kaplan-Meier curves.
RESULTS: In the lung cancer group, ICAM-1, ICAM-2, and VCAM-1 levels in serum and BAL samples were significantly higher compared to the benign and control groups (p < 0.001 for all). BAL ICAM-2 level showed the highest diagnostic performance (AUC: 0.990; sensitivity and specificity: 96.4%). Serum ICAM-2 and ICAM-1 also showed high diagnostic performance. BAL ICAM-1 levels were significantly higher in non-small cell lung cancer (NSCLC) than in small cell lung cancer (SCLC) (p = 0.036). High serum ICAM-1 and BAL ICAM-2 levels were associated with mortality (p = 0.048 and p = 0.015, respectively).
CONCLUSIONS: Serum and BAL levels of ICAM-1, ICAM-2, and VCAM-1 show promise as potential diagnostic biomarkers for lung cancer. Among these, BAL ICAM-2 levels are especially notable due to their high diagnostic accuracy and link to survival.

Keywords:  Biomarker; Bronchoalveolar lavage; Diagnosis; ICAM-1; ICAM-2; Lung cancer; Prognosis; VCAM-1

DOI:  https://doi.org/10.1007/s12094-025-04199-z
Bioorg Chem. 2026 Jan 16. pii: S0045-2068(26)00048-9. [Epub ahead of print]170 109512

Novel 5,7-Diazaindole-based ERK5 inhibitor induces endoplasmic reticulum stress and mitochondrial apoptosis in non-small cell lung Cancer.

Binbin Tian, Yunjie Li, Pengyu Xue, Renhao Chen, Shuo Lv, Luqian He, Gaoyang Lin, Jun Xiao, Lin Long, Guorui Cao, Chuanlong Guo, Longjiang Huang.

  The extracellular signal-regulated kinase 5 (ERK5) signaling pathway represents a promising therapeutic target for non-small cell lung cancer (NSCLC), yet the development of potent and selective inhibitors remains a challenge. Leveraging the 5,7-diazaindole scaffold, a privileged structure in kinase inhibitor discovery, we designed, synthesized, and evaluated a novel series of derivatives as potential ERK5 inhibitors. Among them, compound I1 emerged as the most potent candidate, demonstrating significant anti-proliferative activity against A549 human lung cancer cells with an IC₅₀ of 40.1 μM. Critically, an in vitro kinase assay confirmed that I1 is a direct ERK5 inhibitor, exhibiting potent inhibition of purified ERK5 kinase activity with an IC₅₀ of 403.4 nM. Structure-activity relationship (SAR) studies underscored the critical importance of the unsaturated 1,2,3,6-tetrahydropyridine ring, the amide carbonyl group, and the N1H moiety for optimal activity. Molecular docking revealed that I1 binds robustly within the ERK5 ATP-binding site (PDB: 6HKM), forming key hydrogen bonds with Met140, Asp138, and Asp200, and exhibiting a more favorable binding mode than its analogues. Mechanistic studies indicated that I1 functions as a direct ERK5 inhibitor, suppressing both ERK5 phosphorylation and total protein expression. This ERK5 inhibition triggered a multi-modal anti-tumor mechanism, including the induction of endoplasmic reticulum stress, mitochondrial dysfunction (characterized by reactive oxygen species accumulation and loss of membrane potential), and ultimately, activation of the mitochondrial apoptotic pathway. Importantly, I1 exhibited significant dose-dependent tumor growth suppression in a Lewis lung carcinoma mouse model without causing observable toxicity, highlighting its potential as a promising lead compound for targeted NSCLC therapy.

Keywords:  5,7-Diazaindole derivatives; ERK5 inhibitor; Endoplasmic reticulum stress; Mitochondrial apoptosis; Non-small cell lung cancer

DOI:  https://doi.org/10.1016/j.bioorg.2026.109512
BMJ Open Respir Res. 2026 Jan 20. pii: e003560. [Epub ahead of print]13(1):

Inhibition of GALNT7 suppresses cell proliferation and invasiveness while elevating cell apoptosis via the inactivation of the AKT pathway in non-small cell lung cancer.

Yijian Zhou, Yichen Shi, Jianwei Zhou, Xintao Zhu, Zhiheng Wei, Yiwen Zhang.

   OBJECTIVE: Polypeptide N-acetylgalactosaminyltransferase 7 (GALNT7) is a glycopeptide transferase which is closely involved in the development and progression of cancer. This study aimed to investigate the effects of GALNT7 inhibition on non-small cell lung cancer (NSCLC) cell proliferation, apoptosis and invasiveness and to determine whether these effects are mediated by the protein kinase B (AKT) pathway.
METHODS: Negative control small interfering RNA (siRNA) (si-NC) and siRNA targeting GALNT7 (si-GALNT7) were transfected into A549 and NCI-H1650 cells. Afterwards, the AKT activator '740 Y-P' was added to treat the cells with or without siRNA transfection.
RESULTS: Cell proliferation was reduced after si-GALNT7 transfection compared with si-NC transfection at 24 hours, 48 hours and 72 hours in A549 cells, and at 48 hours and 72 hours in NCI-H1650 cells. Furthermore, the cell apoptosis rate was increased, but the cell invasive number was decreased after si-GALNT7 transfection compared with si-NC transfection in A549 cells and NCI-H1650 cells. Phosphorylated (p)-AKT/AKT expression was lower after si-GALNT7 transfection compared with si-NC transfection in A549 cells and NCI-H1650 cells. Worth noting, the effects of si-GALNT7 transfection on the above-mentioned cell proliferation, apoptosis and invasiveness were repressed by the addition of 740 Y-P in A549 cells and NCI-H1650 cells.
CONCLUSION: GALNT7 inhibition suppresses NSCLC cell proliferation and invasiveness while increasing apoptosis through inactivation of the AKT pathway.

Keywords:  Lung Cancer; Non-Small Cell Lung Cancer

DOI:  https://doi.org/10.1136/bmjresp-2025-003560
Cytokine Growth Factor Rev. 2026 Jan 13. pii: S1359-6101(26)00004-3. [Epub ahead of print]88 47-57

GDF15 in the tumor microenvironment: A central mediator of cancer immunometabolism and therapeutic resistance.

Lingeng Lu, Caroline H Johnson, Sajid A Khan, Melinda L Irwin.

  Growth differentiation factor 15 (GDF15), a divergent member of the transforming growth factor-β (TGFβ) superfamily, has emerged as a pivotal cytokine linking cancer metabolism, immune suppression, and systemic energy balance. Initially characterized as a stress-induced cytokine with roles in appetite regulation and cachexia, GDF15 was first identified in activated macrophages and is also secreted by tumor cells, stromal cells and stressed epithelial cells across multiple tissues. Functionally, GDF15 exerts pleiotropic effects on both immune and nonimmune cell populations, modulating T cells, dendritic cells, and macrophages in the tumor microenvironment (TME), and metabolic tissues such as liver, adipose and muscle, thereby promoting tumor progression, therapeutic resistance, and cancer-associated metabolic dysregulation. In several human cancers of such as colorectal, pancreatic, breast and brain, elevated GDF15 levels correlate with poor prognosis, immune evasion, and chemoresistance. Mechanistically, GDF15 modulates fatty acid metabolism, promotes epithelial-mesenchymal transition, and suppresses anti-tumor immunity by impairing dendritic cell maturation and excluding CD8+ T cell infiltration. Targeting GDF15 may reprogram immunometabolic suppression and enhance checkpoint blockade efficacy. This review synthesizes current knowledge on GDF15's multifaceted roles in tumor biology, emphasizing its function as a central node of cancer immunometabolism. We highlight advances in spatial multi-omics, integrating transcriptomics and immune imaging, that reveal GDF15 spatially restricted immunosuppression in the tumor microenvironment.

Keywords:  Cancer immunotherapy; Colorectal cancer; GDF15; Immunometabolism; Obesity; Pancreatic cancer; Spatial metabolomics; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.cytogfr.2026.01.004