bims-meluca 2026-06-21 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2026–06–21
eight papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Hypoxia/lactate orchestrates the reprogramming metabolism of lung adenocarcinoma by modulating the SIRT2-mediated acetylation.
miR-941 in extracellular vesicles confers anlotinib resistance via Keap1/Nrf2 axis and represents a therapeutic target in non-small cell lung cancer.
Intermediate accumulated upon interruption of fatty acid oxidation flux promotes tumoral ferroptosis and improves immunotherapy.
Targeting the mevalonate pathway with statins overcomes acquired resistance to KRASG12C inhibitors in non-small cell lung cancer.
CDK Inhibition in Lung Cancer Alters Epithelial-Mesenchymal Transition, Autophagy, and Metabolism.
PYCR1 promotes glutamine metabolism and the progression of lung adenocarcinoma by regulating the expression of OPLAH.
Elevated baseline C-reactive protein predicts poorer survival in lung cancer: a 22-year retrospective cohort study.
Analysis of survival and prognostic differences in locally advanced or metastatic non-squamous non-small cell lung cancer with KRAS mutations.

J Transl Med. 2026 Jun 18.

Hypoxia/lactate orchestrates the reprogramming metabolism of lung adenocarcinoma by modulating the SIRT2-mediated acetylation.

Jie Tao, Zhan-Yi Chen, Jing-Na Xun, Meixiang Wang, Juan-Xi Liu, Ying Zhang, Douglas B Lowrie, Yao Li, Xiao-Yong Fan.

   BACKGROUND: Silent information regulator 2 (SIRT2) has been described to have dual roles as an oncogene and tumor suppressor gene in non-small cell lung cancer, but its functional selection and the precise mechanisms of its action remain to be elucidated.
METHODS: lung adenocarcinoma (LUAD) tissue microarrays and cell lines were used to detect SIRT2 expression using Immunohistochemistry and Western blotting. SIRT2 overexpression, knockdown, and knockout LUAD cells were constructed to test SIRT2 function in vitro and in vivo, and targeted metabolomics, proteomics, and acetylation analyses were performed to explore the detailed mechanisms by which SIRT2 affects the biological characteristics of LUAD.
RESULTS: SIRT2 is not only downregulated in LUAD tissues and cells, but also associated with poor prognosis in LUAD patients, not in lung squamous cell carcinoma. We also found that hypoxia-induced increasement in lactate levels led to this decreased SIRT2 expression. Remarkably, SIRT2 deficiency promotes the proliferation and metastasis of LUAD cells in vitro and in vivo, while SIRT2 overexpression exerts the opposite function. Mechanistically, SIRT2 deficiency leaded to increased acetylation levels of multiple enzymes involved in glycolysis, tricarboxylic acid cycle, fatty acid oxidation, and glutaminolysis. And results of co-inmunoprecipitation showed that SIRT2 bound to the above enzymes. Accordingly, SIRT2-deficient LUAD cells showed altered metabolic activities such as glycolysis, pentose phosphate pathway, TCA cycle, serine metabolism, and urea cycle. Notably, SIRT2 deletion increases glycolytic capacity of LUAD cells by increasing the acetylation modification of LDHA at the K118 site.
CONCLUSION: This study reveals that hypoxia-induced lactate elevation decreases SIRT2 expression to promote LUAD progression, with the mechanism related to promoting glycolysis by increasing LDHA acetylation. In addition, decreased SIRT2 expression has also been found to cause alterations in many metabolic pathways with no verification mechanism.

Keywords:  Acetylation; Glycolysis; Lung adenocarcinoma; Oxidative phosphorylation; SIRT2

DOI:  https://doi.org/10.1186/s12967-026-08481-8
Clin Transl Med. 2026 Jun;16(6): e70721

miR-941 in extracellular vesicles confers anlotinib resistance via Keap1/Nrf2 axis and represents a therapeutic target in non-small cell lung cancer.

Aimi Huang, Xiaoqi Li, Erpeng Wu, Menglan Hao, Weimin Wang, Jinjing Xia.

   BACKGROUND: Anlotinib is a multitargeted tyrosine kinase inhibitor for the treatment of advanced non-small cell lung cancer (NSCLC), though its therapeutic efficacy is constrained by acquired resistance. Although elevated extracellular vesicle (EV)-derived miR-941 correlates with anlotinib resistance, its functional role remains unexplored. Here, we provide evidence that EV-delivered miR-941 mediates this resistant phenotype.
METHODS: Functional experiments (gain- and loss-of-function) in A549 and H1299 cells assessed viability, apoptosis and migration. The miR-941/Keap1 interaction was validated using dual-luciferase assays. In vivo resistance was evaluated using wild-type and Keap1 3'UTR-mutant xenograft models. Clinical relevance and survival outcomes were analysed in tumour tissues from anlotinib-treated patients.
RESULTS: EV-derived miR-941 was significantly upregulated in anlotinib-resistant patients. Mechanistically, miR-941 directly targeted the Keap1 3'UTR, suppressing Keap1 protein and activating the Nrf2 signalling pathway. This axis inhibited apoptosis, upregulated anti-apoptotic proteins (Bcl-2, Mcl-1), and promoted malignant phenotypes in vitro. Crucially, in vivo anlotinib resistance induced by miR-941 overexpression was completely abrogated by mutating the Keap1 binding site. Clinical samples confirmed elevated miR-941 and a molecular signature consistent with Keap1 downregulation and Nrf2 activation in resistant tumours. Furthermore, high expression of miR-941 was strongly associated with shorter progression-free survival and overall survival.
CONCLUSION: In this study, we identified EV-derived miR-941 as a key driver of anlotinib resistance via the Keap1/Nrf2 pathway. It represents a promising non-invasive predictive biomarker and serves as a candidate therapy target for overcoming drug-resistant NSCLC.
KEY POINTS: EV-derived miR-941 as a key driver of anlotinib resistance via the Keap1/Nrf2 pathway represent a promising non-invasive predictive biomarker and a potential therapeutic target for overcoming resistance in NSCLC.

Keywords:  Keap1/Nrf2 pathway; anlotinib resistance; extracellular vesicles; miR‐941; non‐small cell lung cancer; predictive biomarker

DOI:  https://doi.org/10.1002/ctm2.70721
Nat Commun. 2026 Jun 17.

Intermediate accumulated upon interruption of fatty acid oxidation flux promotes tumoral ferroptosis and improves immunotherapy.

Yuhan Zhou, Jing Li, Fangfang Liu, Yuan Gao, Songlin Yin, Liguo Yang, Xiaoxiao Li, Junhong Lin, Yan Li, Haotian Shang, Xiang Cheng, Tengfei Chao, Qian Chu, Fujia Lu, Weimin Wang.

Therapeutic strategies targeting cancer metabolism are advancing rapidly. However, perturbing distinct nodes within the same metabolic pathway often yields divergent outcomes. Ferroptosis, a metabolic cell death driven by lipid peroxidation, has garnered attention for potentiating antitumor immunity. Here, we demonstrate that interruption of fatty acid oxidation (FAO) at hydroxyacyl-CoA dehydrogenase (HADHA) node promotes tumoral ferroptosis, whereas targeting upstream enzymes does not. HADHA inhibition causes accumulation of hydroxylated C18 (C18-OH) acylcarnitine to exacerbate mitochondrial lipid peroxidation. In vivo, HADHA ablation or acylcarnitine C18-OH supplementation suppresses tumor growth, enhances antitumor T-cell immunity, and potentiates PD-1 blockade therapy. Clinically, elevated plasma acylcarnitine C18-OH correlates with improved prognosis and immunotherapy response in lung cancer patients. Trimetazidine, an approved anti-ischemic drug and HADHA inhibitor, similarly delays tumor progression and augments immunotherapy. Together, our findings identify HADHA as a ferroptosis regulator and offer a clinically actionable strategy to enhance ferroptosis and immunotherapy through metabolic intervention.

DOI: https://doi.org/10.1038/s41467-026-74430-0
Exp Hematol Oncol. 2026 Jun 18. pii: 52. [Epub ahead of print]15(1):

Targeting the mevalonate pathway with statins overcomes acquired resistance to KRASG12C inhibitors in non-small cell lung cancer.

Weihao Lin, Qi-An Chen, Yannan Yang, Yibo Gao, Jie He.

  The emergence of covalent KRASG12C inhibitors has revolutionized the treatment of non-small cell lung cancer (NSCLC), yet acquired resistance remains a major clinical challenge. Here, we systematically identified statins as potent agents capable of overcoming acquired resistance to KRASG12C inhibitors through high-throughput screening of 1,971 FDA-approved compounds. Statin treatment preferentially induced cell death in resistant cells, markedly impairing tumor growth both in vitro and in vivo. Proteomic profiling and pathway analysis revealed upregulation of the mevalonate (MVA) pathway in resistant cells. Genetic silencing of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and pharmacologic inhibition of the MVA-geranylgeranyl pyrophosphate (GGPP) branch recapitulated the effects of statins. Mechanistically, MVA-GGPP signaling promoted Yes-associated protein (YAP) activation, whereas disruption of this axis by statins or geranylgeranyl transferase I (GGTase-I) inhibitors impaired YAP-driven transcription and cell survival. Combination therapy with simvastatin and KRASG12C inhibitors delayed resistance onset and enhanced antitumor efficacy across multiple in vivo models, with acceptable tolerability. These findings identify the MVA-GGPP-YAP pathway as a therapeutic vulnerability in acquired KRASG12C inhibitor resistance and support repurposing statins to improve KRASG12C-targeted therapy.

Keywords:  Acquired resistance; KRASG12C inhibitor; Mevalonate pathway; Non-small cell lung cancer; Statin

DOI:  https://doi.org/10.1186/s40164-026-00797-x
Curr Cancer Drug Targets. 2026 Jun 16.

CDK Inhibition in Lung Cancer Alters Epithelial-Mesenchymal Transition, Autophagy, and Metabolism.

Azizeh Alsayyid, Rose Ghemrawi, Nour Sammani, Azza Ramadan, Sedra Kremesh, Molham Sakkal, Nosayba Aldamook, Walaa K Mousa, Mostafa Khair.

   INTRODUCTION: Lung cancer remains the leading cause of cancer-related mortality worldwide, responsible for over 1.8 million deaths annually. Despite therapeutic advancements, clinical outcomes in advanced lung adenocarcinoma (LUAD) remain poor due to treatment resistance and metastasis. Cyclin-dependent kinases (CDKs) are essential regulators of cell cycle progression and transcription, yet their therapeutic targeting-especially beyond CDK4 and CDK6-has been largely underexplored in lung cancer. This study investigates the oncogenic relevance of CDK1, CDK2, CDK5, CDK7, and CDK9 in LUAD and evaluates the effects of two pharmacological CDK inhibitors: Roscovitine (a broad-spectrum CDK inhibitor) and RO-3306 (a CDK1-selective inhibitor).
METHODS: Gene expression levels of CDK family members were analyzed using the UALCAN tool, based on the Cancer Genome Atlas (TCGA) LUAD dataset. LUAD cell lines A549 and H292 were treated with Roscovitine and RO-3306 at various concentrations and durations. Cell viability was assessed using the MTT assay; migration was evaluated through wound healing assays. Protein expression of autophagy markers, epithelial-to-mesenchymal transition marker, and metabolic stress markers was assessed by Western blotting.
RESULTS: Bioinformatic analysis revealed significant overexpression of CDK1, CDK2, CDK5, CDK7, and CDK9 in LUAD compared to normal lung tissue. Both inhibitors reduced cell viability in a dose- and time-dependent manner, with Roscovitine demonstrating greater potency. Notably, Roscovitine significantly suppressed cell migration and upregulated E-cadherin expression, suggesting reversal of epithelial-to-mesenchymal transition. Additionally, Roscovitine induced complete autophagic flux, as shown by LC3-II accumulation and p62 degradation, along with activation of metabolic stress pathways. In contrast, RO-3306 selectively impaired migration only in H292 cells and triggered incomplete autophagy, indicating a more limited mechanistic effect.
DISCUSSION: This study identifies CDK1, CDK2, CDK5, CDK7, and CDK9 as overexpressed and actionable targets in LUAD. Importantly, it reveals for the first time that CDK inhibition- particularly via Roscovitine-modulates both cell migration and autophagy through distinct and potent mechanisms.
CONCLUSION: These findings support the further development of multi-target CDK inhibitors as promising candidates to overcome tumor progression and therapeutic resistance in lung cancer.

Keywords:  CDK inhibition; Lung cancer; autophagy; metastasis; roscovitine; RO-3306; targeted therapy; tumor metabolism

DOI:  https://doi.org/10.2174/0115680096414298251201033358
Clin Exp Med. 2026 Jun 15.

PYCR1 promotes glutamine metabolism and the progression of lung adenocarcinoma by regulating the expression of OPLAH.

Wei Chen, Kai Wang, Renyu Wang, Xufeng Deng, Xiaobing Liu, Peng Dai, Quanxing Liu.

  Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer. Glutamine plays a critical role in the progression of LUAD. However, the function of pyrroline-5-carboxylate reductase 1 (PYCR1) and its regulatory role in glutamine metabolism remain unclear. Transcriptomic and clinical data for LUAD were obtained from The Cancer Genome Atlas (TCGA) and validated using Gene Expression Omnibus (GEO) datasets (GSE19188, GSE13213). Glutamine metabolism-related genes were analyzed for differential expression and prognostic significance. Functional enrichment was performed via gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) analyses. Single-cell RNA-seq data (GSE117570) were processed using Seurat, and cell-cell communication was inferred with CellChat. In vitro, lentiviral overexpression, Western blotting, EdU, CCK-8, and glutamine uptake assays were conducted. An orthotopic xenograft model was established in nude mice to assess tumor growth in vivo. Six glutamine-metabolism-related genes were found significantly overexpressed in LUAD tissues and associated with poor overall survival. Single-cell sequencing revealed predominant PYCR1 expression in malignant cells. Functional assays demonstrated that PYCR1 overexpression enhanced glutamine uptake, proliferation, and inhibited apoptosis in LUAD cells, effects mediated via suppression of the P53 pathway. PYCR1 promoted tumor growth in a xenograft model and was found to transcriptionally upregulate 5-oxoprolinase (OPLAH), which augmented its oncogenic effects. Our findings identify the PYCR1/OPLAH axis as a key driver of LUAD progression via p53 signaling, revealing a promising therapeutic target.

Keywords:  5-oxoprolinase; Glutamine; Lung adenocarcinoma; pyrroline-5-carboxylate reductase 1

DOI:  https://doi.org/10.1007/s10238-026-02181-9
Transl Lung Cancer Res. 2026 May 31. 15(5): 123

Elevated baseline C-reactive protein predicts poorer survival in lung cancer: a 22-year retrospective cohort study.

Xiaomin Wei, Xiaoyan Liu, Mei Li, Hanping Wang, Wei Zhong, Xiaotong Zhang, Xiaoxing Gao, Mengzhao Wang, Xuefei Wu, Meng Rui, Ruzetuoheti Yiminniyaze, Xiaoyan Si, Li Zhang.

   Background: Systemic inflammation has been implicated in cancer progression and C-reactive protein (CRP) is an established inflammatory biomarker. We investigated clinical and pathological factors associated with elevated baseline CRP in lung cancer and evaluated their relationships with survival outcomes.
Methods: We retrospectively reviewed 1,339 patients with newly diagnosed lung cancer at Peking Union Medical College Hospital (PUMCH) between October 2000 and March 2022. Baseline serum CRP was measured prior to anti-tumor therapy; CRP ≥10 mg/L was defined as elevated. Patient demographics, tumor characteristics and treatment variables were compared by CRP level. Overall survival (OS) and progression-free survival (PFS) were assessed using Kaplan-Meier analysis with log-rank tests. Cox proportional hazards models were used to identify independent prognostic factors for OS and PFS. The study was approved by the ethical review committee of PUMCH.
Results: Elevated CRP (≥10 mg/L) was present in 41.0% of patients at diagnosis. High CRP was significantly associated with adverse clinical features, including older age, male sex, smoking, alcohol use, advanced stage III-IV disease, Eastern Cooperative Oncology Group (ECOG) performance status score 2-4, absence of driver gene mutations, positive programmed death ligand 1 (PD-L1) expression, presence of metastases and receipt of immunotherapy. In Kaplan-Meier analyses, patients with high CRP had significantly shorter OS and PFS than those with CRP <10 mg/L (median OS 19.0 vs. 44.0 months; 5-year OS 15.8% vs. 37.2%; median PFS 8.0 vs. 12.0 months; 2-year PFS 12.2% vs. 23.1%, respectively; log-rank P<0.001 for both). In multivariate Cox analysis adjusting for age, sex, smoking, comorbidities, histology, stage, performance status and metastasis, baseline CRP ≥10 mg/L remained an independent predictor of worse OS and PFS.
Conclusions: Baseline CRP elevation in lung cancer correlates with more aggressive disease characteristics and independently portends inferior survival. CRP, as an inexpensive routine test, could aid in risk stratification and prognostication. Integrating CRP into clinical decision-making may improve identification of high-risk patients who might benefit from intensified or alternative therapeutic strategies.

Keywords:  C-reactive protein (CRP); Lung cancer; biomarker; inflammation; prognosis

DOI:  https://doi.org/10.21037/tlcr-2026-1-0118
J Thorac Dis. 2026 May 31. 18(5): 489

Analysis of survival and prognostic differences in locally advanced or metastatic non-squamous non-small cell lung cancer with KRAS mutations.

Xiangyu Du, Shanxin Zhang, Yahui Lv, Zhefeng Liu.

   Background: Among Eastern populations, the occurrence of Kirsten rat sarcoma viral oncogene (KRAS) mutations in non-small cell lung cancer (NSCLC) is around 10% to 15%. Despite being approved for marketing, targeted drugs are recommended by the Chinese Society of Clinical Oncology (CSCO) Guidelines only as a second-line option, and the selection of first-line treatment regimens remains to be verified. The purpose of this study is to explore the effectiveness of various initial treatment plans for NSCLC with KRAS mutations in real-world settings.
Methods: The study reviewed the clinical data of 180 patients with KRAS mutation-positive locally advanced or metastatic non-squamous NSCLC treated at the Chinese People's Liberation Army (PLA) General Hospital over the previous decade. The patients were categorized based on their initial treatment plans to compare therapeutic efficacy and prognosis, and the relevant influencing factors were analyzed.
Results: In the 180 patients, median progression-free survival (mPFS) was 8.60 months and median overall survival (mOS) was 17.47 months. Immune checkpoint inhibitors plus chemotherapy (ICIs + CHE) showed the best efficacy, with mPFS 11.30 months, mOS 21.24 months, objective response rate (ORR) 39.29%, and disease control rate (DCR) 89.29%. ICIs included standard programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) antibodies, chemotherapy was platinum-based doublet therapy, and anti-angiogenic therapy was limited to bevacizumab (BEV). This study directly compared ICIs + CHE with the triple combination (ICIs + CHE + BEV) to fill an existing research gap. The ICIs + CHE group had significantly better progression-free survival (PFS) than ICIs or CHE alone, and better overall survival (OS) than CHE alone. Adding anti-angiogenic therapy to ICIs + CHE provided no significant additional benefit. Different level of PD-L1 expression did not affect PFS or OS in immunotherapy-based regimens. In univariate and multivariate analyses, age and gender did not influence PFS; high Eastern Cooperative Oncology Group (ECOG) performance status and bone metastasis were associated with OS. Baseline characteristics were generally comparable across groups, with only minor differences in age, brain metastasis, and PD-L1 expression (P<0.05), which did not independently predict survival.
Conclusions: ICIs + CHE is the preferred first-line treatment regimen for patients with locally advanced/metastatic KRAS-mutant non-squamous NSCLC, and the addition of anti-angiogenic agents does not improve therapeutic efficacy. Clinical treatment regimens should be selected individually based on patient characteristics and PD-L1 expression level did not serve as a survival stratification factor for immunotherapy-based treatment regimens.

Keywords:  Kirsten rat sarcoma viral oncogene (KRAS); Non-squamous non-small cell lung cancer (non-squamous NSCLC); first-line treatment regimens

DOI:  https://doi.org/10.21037/jtd-2026-0522