bims-meluca 2026-05-10 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2026–05–10
six papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Subcutaneous adipose tissue radiodensity as a prognostic marker in metastatic non-small cell lung cancer treated with immune checkpoint inhibitors.
Characterization and therapeutic suppression of KEAP1-NRF2-driven resistance to KRAS inhibitors in pancreatic and lung cancer.
PCK2 Promotes Non-Small Cell Lung Cancer Progression via SLC38A2- Mediated Glutamine Uptake and mTORC1 Activation.
GLUT6-facilitated noncanonical glucose metabolic rewiring enables resistance to targeted cancer therapy.
Exosomal 3'tiRNA-PheGAA and interleukin-6 as novel biomarkers for non-invasive detection of NSCLC.
YAP1 silencing enhances cisplatin efficacy in lung adenocarcinoma via activating mitochondrial apoptosis.

Contemp Oncol (Pozn). 2026 ;30(1): 47-55

Subcutaneous adipose tissue radiodensity as a prognostic marker in metastatic non-small cell lung cancer treated with immune checkpoint inhibitors.

Yuliia Moskalenko, Viktor Kovchun, Anton Bohdanov, Vitalii Budko.

   Introduction: Radiodensity of subcutaneous adipose tissue (SAT), measurable on routine computed tomography (CT), may reflect metabolic status and cachexia, both of which influence cancer outcomes. However, its prognostic role in metastatic non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICI) remains unclear. This study aimed to evaluate the prognostic value of SAT radiodensity in this patient population.
Material and methods: The retrospective analysis included 92 patients with stage IV NSCLC receiving ICI. Subcutaneous adipose tissue radiodensity (Hounsfield units) was measured from pre-treatment CT at the L3 level and categorized into quartiles. Kaplan- Meier analysis, log-rank test, and Cox proportional hazards models were used. Nonlinear associations were assessed using restricted cubic splines. Cox models were? adjusted for demographic, clinical, and treatment factors. A p-value < 0.05 was considered statistically significant.
Results: Median overall survival for Q1, Q2, Q3, and Q4 was 13.4, 26.3, 18.4, and 14.2 months, respectively (log-rank p = 0.0226). Compared with Q1, Q2 showed a significantly reduced mortality risk across all models (fully adjusted hazard ratios = 0.32, 95% CI: 0.15-0.64, p = 0.002). Q3 and Q4 were not significantly different from Q1. Restricted cubic spline analysis revealed a mild U-shaped relationship (p for nonlinearity = 0.0094), with intermediate SAT density linked to best outcomes. Programmed death ligand 1 expression significantly modified the SAT-survival association (p for interaction < 0.0001).
Conclusions: Moderate SAT radiodensity was associated with improved survival in metastatic NSCLC patients on ICI, potentially reflecting an optimal metabolic-immune balance. Subcutaneous adipose tissue density, easily obtained from routine imaging, warrants further prospective validation as a scalable prognostic biomarker.

Keywords:  body composition; immune checkpoint inhibitors; mortality; non-small cell lung cancer; subcutaneous adipose tissue

DOI:  https://doi.org/10.5114/wo.2026.159311
bioRxiv. 2026 Apr 21. pii: 2026.04.18.719329. [Epub ahead of print]

Characterization and therapeutic suppression of KEAP1-NRF2-driven resistance to KRAS inhibitors in pancreatic and lung cancer.

Wen-Hsuan Chang, Alec J Vaughan, Addison G Stamey, Mariana Mancini, Makiko Hayashi, Runying Yang, Ryan Robb, Daniel Andrussier, Jeffrey A Klomp, Andrew M Waters, Antje Schaefer, Brian M Wolpin, Kirsten L Bryant, Adrienne D Cox, Fernando Moreira Simabuco, Kwok-Kin Wong, Andrew J Aguirre, Clint A Stalnecker, Thales Papagiannakopoulos, Channing J Der.

The recent approval of KRAS inhibitors supports the therapeutic value of targeting mutant KRAS cancers. However, clinical efficacy is hindered by both primary and treatment-associated acquired resistance. We applied a CRISPR-Cas9 loss-of-function screen and identified loss of KEAP1 as a resistance mechanism to the KRAS G12D -selective inhibitor MRTX1133 and the RAS(ON) multi-selective inhibitor RMC-7977 in pancreatic cancer models. RNA-sequencing analyses revealed a KEAP1 KO transcriptome that is distinct from the ERK-, MYC-, and YAP/TAZ-TEAD-dependent transcriptional programs that drive KRAS inhibitor resistance, demonstrating a distinct mechanism of resistance. We then established a PDAC KEAP1-deficient (PKD) gene signature that was enriched in patients and preclinical models insensitive to KRAS inhibitor treatment. Finally, we observed that KEAP1-deficient cells exhibited elevated glutamine metabolism, and combination treatment with the glutamine antagonist DRP-104 (sirpiglenastat) enhanced KRAS inhibitor suppression of pancreatic and lung tumors.
SIGNIFICANCE: KEAP1 loss is associated with reduced response to KRAS inhibitor therapy. We demonstrate that KEAP1 loss-associated resistance can be overcome by pharmacologic inhibition of the KEAP1 loss-induced glutamine dependency, establishing a combination to enhance RAS inhibitor clinical efficacy.

DOI: https://doi.org/10.64898/2026.04.18.719329
Curr Cancer Drug Targets. 2026 Apr 28.

PCK2 Promotes Non-Small Cell Lung Cancer Progression via SLC38A2- Mediated Glutamine Uptake and mTORC1 Activation.

Libo Ruan, Fan Zhang, Ling Xiao, Minjun Zhao, Kewang Xu, Wenjun Zeng, Haiyan Zhang.

   INTRODUCTION/OBJECTIVE: Phosphoenolpyruvate carboxykinase 2 (PCK2) contributes to cancer metabolic adaptation, yet its role in glutamine (Gln) transport and downstream signaling in non-small cell lung cancer (NSCLC) under glucose deprivation is unclear. This study aimed to investigate the PCK2-SLC38A2-mTORC1 axis in NSCLC under metabolic stress.
METHODS: A549 NSCLC cells were subjected to PCK2 knockdown using shRNA. Glutamine transporter expression was assessed via PRM proteomics and Western blot. Proliferation, migration, apoptosis, mTORC1 activity, and autophagy were analyzed under low-glucose conditions. Rescue assays were performed using Gln supplementation or SLC38A2 overexpression. Expression of PCK2 and SLC38A2 was evaluated in NSCLC tissues using immunohistochemistry.
RESULTS: PCK2 knockdown reduced Gln transporter levels, especially SLC38A2, and impaired cell proliferation and migration, while inducing apoptosis under low-glucose conditions. These effects were reversed by Gln supplementation or SLC38A2 overexpression. Mechanistically, PCK2 knockdown suppressed mTORC1 signaling and disrupted autophagy flux, both of which were restored by SLC38A2. Clinically, high expression of PCK2 and SLC38A2 was observed in NSCLC tissues and correlated with poor prognosis. Experimental results from both NSCLC patient-derived samples and tissue models demonstrated that downregulation of PCK2 effectively attenuated the progression of non-small cell lung cancer.
DISCUSSION: PCK2 promoted NSCLC cell survival and progression by maintaining Gln uptake through SLC38A2, thereby activating mTORC1 and modulating autophagy. These findings support a metabolic adaptation mechanism critical to tumor aggressiveness.
CONCLUSION: The PCK2-SLC38A2-mTORC1 signaling axis sustains NSCLC cell viability under glucose limitation and represents a potential metabolic vulnerability for therapeutic targeting.

Keywords:  Non-small cell lung cancer (NSCLC); PCK2; SLC38A2; glutamine transport; low glucose; mTORC1

DOI:  https://doi.org/10.2174/0115680096423756251125052704
Nat Commun. 2026 May 07.

GLUT6-facilitated noncanonical glucose metabolic rewiring enables resistance to targeted cancer therapy.

Huimin Lei, Ruixue Xia, Yabin Tang, Jun Lu, Chan Xiang, Yujing Li, Hongyu Liu, Peichen Zou, Ayinazhaer Aihemaiti, Wei Zhang, Ying Shen, Baohui Han, Yuchen Han, Hua Zhong, Hongzhuan Chen, Liang Zhu.

Targeting glucose metabolism has long been pursued as an anticancer strategy, yet its clinical translation remains challenging. Achieving therapeutic selectivity requires identifying actionable metabolic distinctions between different malignant traits. Here, we uncover a noncanonical, lactate-independent glucose metabolic pathway facilitated by the glucose transporter 6 (GLUT6), which confers targeted therapy resistance in lung cancer. Downstream, GLUT6 promotes glucose influx and diversion toward methylglyoxal production, leading to kelch-like ECH-associated protein 1 (KEAP1) dimerization and nuclear factor erythroid 2-related factor 2 (NRF2) pathway activation, driving resistance. Upstream, GLUT6 expression is transcriptionally upregulated by therapy-induced MYC associated zinc finger protein (MAZ) activation. Targeting GLUT6 prevents and overcomes EGFR and KRAS inhibitors resistance. Moreover, the MAZ-GLUT6-NRF2 axis correlates with clinical treatment response and relapse. The preferential reliance on GLUT6-a noncanonical transporter with minimal systemic homeostasis perturbation-highlights its promise as a target for overcoming resistance and revitalizing glucose metabolism-based anticancer strategies.

DOI: https://doi.org/10.1038/s41467-026-72922-7
Discov Oncol. 2026 May 02.

Exosomal 3'tiRNA-PheGAA and interleukin-6 as novel biomarkers for non-invasive detection of NSCLC.

Ning Yuan, Qun Zhang, Jing Shi, WenJun Cheng, Bin Zhao, Zhijun Zhang.

   BACKGROUND: Non-small cell lung cancer (NSCLC) remains one of the leading causes of cancer-related mortality worldwide. However, the diagnostic sensitivity and specificity of commonly used tumor markers, such as carcinoembryonic antigen (CEA) and cytokeratin-19 fragment (CYFRA21-1), remain limited. This study aimed to evaluate the diagnostic value of serum exosomal 3'tiRNA-PheGAA and interleukin-6 (IL-6), alone and in combination with conventional tumor markers, for the detection of NSCLC.
METHODS: Peripheral blood samples were collected from 110 patients with NSCLC and healthy controls. Serum exosomes were isolated, and the expression of 3'tiRNA-PheGAA was measured using quantitative real-time polymerase chain reaction (qRT-PCR). Serum levels of CEA, CYFRA21-1, and IL-6 were determined by electrochemiluminescence immunoassay (ECLIA). The diagnostic performance of individual and combined biomarkers was evaluated using receiver operating characteristic (ROC) curve analysis.
RESULTS: Serum levels of 3'tiRNA-PheGAA, IL-6, CEA, and CYFRA21-1 were significantly higher in NSCLC patients than in healthy controls (P < 0.0001). ROC analysis showed that the area under the curve (AUC) values for 3'tiRNA-PheGAA and IL-6 were 0.680 and 0.898, respectively. The combination of 3'tiRNA-PheGAA and IL-6 increased the AUC to 0.926, while the four-marker panel (3'tiRNA-PheGAA, IL-6, CEA, and CYFRA21-1) achieved the highest diagnostic performance with an AUC of 0.971.
CONCLUSIONS: Serum exosomal 3'tiRNA-PheGAA and IL-6 may serve as promising non-invasive biomarkers for NSCLC diagnosis, and their combination with conventional tumor markers significantly improves diagnostic accuracy.

Keywords:  Biomarker; CEA; CYFRA21-1; IL-6; ROC; tiRNA

DOI:  https://doi.org/10.1007/s12672-026-05141-7
Biomater Adv. 2026 May 03. pii: S2772-9508(26)00225-6. [Epub ahead of print]186 214927

YAP1 silencing enhances cisplatin efficacy in lung adenocarcinoma via activating mitochondrial apoptosis.

Renfeng Xu, Saifan Zeng, Ting Zhang, Jingjing Wu, Juan Tang, Hongqin Yang, Feng Gao.

  Lung adenocarcinoma (LUAD) remains one of the leading causes of cancer-related deaths worldwide, and cisplatin (DDP) resistance severely limits the efficacy of first-line chemotherapy. Extracellular matrix (ECM) stiffening is a hallmark of solid tumors, yet how it modulates chemosensitivity remains unclear. This study demonstrates that matrix stiffness activates the mechanosensor YAP1 in lung adenocarcinoma, which in turn establishes an apoptosis-refractory state by upregulating Bcl2 and downregulating Bax. Functional experiments establish the YAP1-Bax axis as the core pathway, while clinical correlation analysis reveals that YAP1 expression significantly predicts poor post-chemotherapy survival. Our findings reveal a mechanism by which mechanical cues desensitize mitochondrial apoptosis through YAP1-driven transcriptional reprogramming, providing both new insights into chemoresistance mechanisms and a potential biomarker for treatment response.

Keywords:  Cell apoptosis; Cisplatin; LUAD; Matrix stiffness; Yes-associated protein 1

DOI:  https://doi.org/10.1016/j.bioadv.2026.214927