bims-meluca 2026-01-11 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2026–01–11
ten papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

IL-17D promotes ferroptosis resistance in lung cancer via activating PPARγ pathway.
‌PPIA regulates fatty acid and glutamine metabolism in lung adenocarcinoma based on multiomics prognostic model and experiment validation.
A novel pan class-I glucose transporter inhibitor DRB18 exhibits synergistic effects with paclitaxel in vitro and in vivo against human non-small cell lung cancer.
Lactylation of HK2 facilitates cisplatin resistance in NSCLC by promoting cell migration, invasion, and glycolysis.
Integrative Single-Cell and Machine Learning Analysis Identifies a Nucleotide Metabolism-Related Signature Predicting Prognosis and Immunotherapy Response in LUAD.
Inflammatory-Molecular Clusters as Predictors of Immunotherapy Response in Advanced Non-Small-Cell Lung Cancer.
O-GlcNAcylation levels predict radiotherapy outcome in non-small cell lung cancer.
Lung Cancer Cells Secrete Glutamine to Accumulate Tumor-Associated Macrophages.
MiR-31 suppresses lung adenocarcinoma cell proliferation through CDK1 and E2F2-mediated cell cycle arrest.
PDK1 and YAP1/TEAD signaling drive acquired KRAS inhibitor resistance in KRAS-mutant non-small cell lung cancer.

Free Radic Biol Med. 2026 Jan 05. pii: S0891-5849(26)00005-5. [Epub ahead of print]245 343-356

IL-17D promotes ferroptosis resistance in lung cancer via activating PPARγ pathway.

Wei Du, Xiaofan Feng, Yaru Liu, Xueying Li, Yuqing Ouyang, Haoke Zhang, Zihe Liu, Xiaona Lu, Siyu Cai, Chunyan Yu, Qianrui Liu, Weimin Deng.

  Despite significant advancements in targeted therapy and immunotherapy that have markedly improved the survival of patients with non-small cell lung cancer (NSCLC), challenges such as tumor heterogeneity and therapeutic resistance persist. Ferroptosis, a unique form of iron-dependent programmed cell death driven by lipid peroxidation, has emerged as a promising therapeutic target for cancer treatment. Interleukin-17D (IL-17D), a member of the IL-17 cytokine family, is involved in regulating immune cell responses within the tumor microenvironment. However, its role in ferroptosis remains unclear. In this study, we demonstrated that high IL-17D expression in lung cancer cell lines is significantly associated with ferroptosis resistance and predicts poor prognosis of patients with lung cancer. Mechanistically, IL17D overexpression promotes the expression of ferroptosis resistance-related genes by enhancing the accessibility of nuclear transcription factor Y (NFY) complex binding sites, and reduces intracellular lipid peroxidation levels. Notably, upon treatment with ferroptosis inducers, IL-17D significantly upregulates peroxisome proliferator-activated receptor gamma (PPARγ) expression, promotes cellular lipid droplet accumulation, and elevates ATP levels in lung cancer cells. Importantly, pharmacological inhibition of the PPARγ pathway reverses IL-17D-induced ferroptosis resistance. Collectively, these findings uncover a novel mechanism whereby IL-17D regulates ferroptosis through PPARγ-dependent lipid metabolic reprogramming, highlighting the IL-17D-PPARγ axis as a promising therapeutic target to overcome ferroptosis resistance in lung cancer.

Keywords:  Ferroptosis resistance; IL-17D; Lipid peroxidation; Lung cancer; NFYA; PPARγ

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.01.005
Sci Rep. 2026 Jan 05.

‌PPIA regulates fatty acid and glutamine metabolism in lung adenocarcinoma based on multiomics prognostic model and experiment validation.

Yuan Gan, Wanshuo Wei, Bowei Jiang, Xindan Zhang, Lin Jiang, Liangsen Teng, Xiaomei Xie, Yixin Liu, Qiumei Xie, Lihe Jiang.

  Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer worldwide, in which fatty acid metabolism plays a key role in tumor growth, metastasis, and immune evasion. PPIA has been confirmed to be closely related to tumor metabolism and immune regulation, but its specific mechanism of action is still unclear. Multi-omics data from TCGA and GEO, combined with single-cell RNA sequencing (scRNA-seq), were used to characterize metabolic heterogeneity and the immune microenvironment in lung adenocarcinoma (LUAD). Fatty acid metabolism-related genes were identified via WGCNA and univariate Cox regression, and a prognostic risk model was constructed. Virtual knockout, cell function assays, and metabolic profiling were performed to investigate the role of PPIA in metabolic reprogramming and tumor progression. In vitro, PPIA was silenced using siRNA or co-overexpressed with pCMV-C-Myc in A549 and H1975 cells. Functional validation included qRT-PCR and Western blotting, as well as CCK-8, colony formation, wound healing, and Transwell assays to assess proliferation, migration, and invasion. Metabolic assays measured glutamine uptake, α-ketoglutarate production, free fatty acid levels, and the GSH/GSSG ratio, elucidating PPIA's regulatory effects on metabolism and LUAD progression. Integrative multi-omics analysis identified a fatty acid metabolism-related gene module associated with poor prognosis in LUAD. A four-gene risk model (ERCC1, KYNU, AKR1A1, and PPIA) demonstrated strong predictive power for overall survival across multiple datasets. Single-cell analysis revealed that PPIA was highly expressed in malignant, metabolically active cell populations and strongly correlated with fatty acid and glutamine metabolism. Functional assays confirmed that PPIA silencing inhibited LUAD cell proliferation, migration, and EMT, while reducing key metabolites including glutamine uptake, α-ketoglutarate, free fatty acids, and the GSH/GSSG ratio. Mechanistically, PPIA depletion downregulated c-Myc expression, whereas c-Myc overexpression partially reversed these effects, suggesting that PPIA drives LUAD progression through the c-Myc-mediated fatty acid-glutamine metabolic axis. This study reveals that PPIA promotes the malignant progression of LUAD and affects the immune microenvironment by regulating the c-Myc-mediated fatty acid-glutamine metabolism network remodeling. A prognosis model based on fatty acid metabolism can serve as an effective tool for assessing the prognosis of LUAD patients. Due to incomplete clinical information in some datasets, comprehensive subgroup analyses could not be performed.

Keywords:  Fatty acid metabolism; Glutamine metabolism; Lung adenocarcinoma; Multiomics; Prognostic factor

DOI:  https://doi.org/10.1038/s41598-025-34313-8
bioRxiv. 2025 Dec 31. pii: 2024.12.15.628558. [Epub ahead of print]

A novel pan class-I glucose transporter inhibitor DRB18 exhibits synergistic effects with paclitaxel in vitro and in vivo against human non-small cell lung cancer.

Pratik Shriwas, Lindsey Bachmann, Ryan Ward, Subhodip Adhicary, Corinne M Nielsen, Yunsheng Li, Haiyun Zhang, Jingwen Song, Dennis Roberts, Stephen Bergmeier, Xiaozhuo Chen.

Background Cancer cells depend on glucose for biomass synthesis, cell proliferation, and drug resistance. Glucose transporter (GLUT) transcripts as well as proteins are upregulated in human lungs and other cancers and are negatively correlated with patient survival, particularly GLUT1 and GLUT3. Thus, inhibiting GLUT function has been an attractive anticancer strategy. We previously characterized WZB117 and DRB18, first- and second-generation pan-class I GLUT inhibitors, respectively. DRB18 strongly inhibits glucose transport mediated by GLUT1-4 in non-small lung cancer (NSCLC) A549 cells in vitro and in vivo . Here, we report DRB18 as a more stable and potent anticancer compound, compared to WZB117.
Methods: Immunohistochemistry analysis was performed in Lung adenocarcinoma (LUAD) tissue array to investigate GLUT1 and GLUT3 protein expression between normal, lower and higher stage LUAD patients. Bioinformatics analysis was performed to examine additive effect of GLUT3 to GLUT1 mediated prognosis in LUAD. Glucose uptake and resazurin dye-based proliferation assays were used to determine glucose uptake inhibitory and cell proliferation inhibitory against panel of human cancer cell lines A549, Panc1 and Hela. DRB18 potency was tested against the presence of extracellular nutrients glucose, glutamine and ATP. Synergism between DRB18 and clinically approved anticancer drugs was tested against cancer cells. DRB18 and advanced NSCLC drug Paclitaxel were tested for synergy in vitro and in vivo .
Results: GLUT1/3 combination exhibited higher hazard ratio than either GLUT1 and GLUT3 alone in many cancer types including LUAD. DRB18 reduced glucose uptake in NSCLC A549, pancreatic Panc1, and cervical Hela cancer cells with varied but strong anticancer potencies in the presence or absence of extracellular nutrients such as ATP and glucose. Combined with different clinical and pre-clinical anticancer compounds such as V9302, CB839, Sutent, Brigatinib, DRB18 significantly increased death of A549 and Panc1 cells. Noteworthy, DRB18 exhibited strong anticancer synergy with paclitaxel, an approved chemo drug for NSCLC, drastically reducing cancer cell proliferation in vitro and growth of A549 tumors grafted on the flank of nude mice without significant side effects, compared to single drug treatments. Mechanistically, DRB18 treatment with paclitaxel elevated the expression of Caspases 3 and 9, suggesting GLUT-inhibiting and apoptosis-inducing anticancer mechanisms of DRB18 with paclitaxel.
Conclusions: Collectively, our results demonstrate anticancer efficacy of pan class-I GLUT inhibitor DRB18 in combination with paclitaxel, providing a potentially more efficacious therapeutic strategy for treating advanced NSCLC and other cancers.

DOI: https://doi.org/10.1101/2024.12.15.628558
Pathol Res Pract. 2025 Dec 29. pii: S0344-0338(25)00542-4. [Epub ahead of print]279 156349

Lactylation of HK2 facilitates cisplatin resistance in NSCLC by promoting cell migration, invasion, and glycolysis.

Fanrui Zeng, Wenyang Wang, Peng Liu, Qingsi Zeng.

   OBJECTIVE: Cisplatin (DDP) resistance has markedly diminished the efficacy of DDP-based chemotherapy in non-small cell lung cancer (NSCLC). Glycolysis represents a key contributor to NSCLC progression. Lactylation, a novel epigenetic modification, directly regulates glycolysis-associated gene expression. This study aimed to investigate whether lactylation-mediated modulation of glycolytic genes contributes to DDP resistance in NSCLC.
METHODS: Cell viability, migration, and invasion capacities in parental and resistant NSCLC cells were assessed using cell counting kit-8 and Transwell migration/invasion assays. RT-qPCR and Western blot analyses were employed to quantify mRNA and protein levels of glycolytic markers. A xenografted tumor model was established to evaluate in vivo tumor progression.
RESULTS: DDP-resistant NSCLC cells exhibited elevated glycolysis activity and increased lactylation levels of hexokinase 2 (HK2). Moreover, HK2 lysine lactylation (Kla) and protein stability were enhanced in resistant cells through suppression of ubiquitination. Functional experiments demonstrated that HK2 downregulation inhibited cell viability, migration, invasion, and glycolytic metabolism in A549/DDP and H1229/DDP cells, with these effects being reversed following sodium lactate treatment. Crucially, the glycolytic inhibitor 2-deoxy-D-glucose (2-DG) abrogated this rescue, and a K873R lactylation-deficient mutant failed to restore the malignant phenotype, confirming the specificity of the mechanism. In vivo studies further confirmed that HK2 inhibition suppressed tumor growth.
CONCLUSIONS: Lactylation at K873 stabilized HK2 by inhibiting its ubiquitination, which in turn drove glycolytic flux and promoted malignant behaviors in DDP-resistant NSCLC. This HK2 lactylation-stabilization axis represents a novel mechanism underlying chemoresistance and a promising therapeutic target for overcoming DDP resistance in NSCLC.

Keywords:  DDP resistance; Glycolysis; HK2; Invasion; Lactylation; Migration; Non-small cell lung cancer

DOI:  https://doi.org/10.1016/j.prp.2025.156349
Cancers (Basel). 2026 Jan 02. pii: 160. [Epub ahead of print]18(1):

Integrative Single-Cell and Machine Learning Analysis Identifies a Nucleotide Metabolism-Related Signature Predicting Prognosis and Immunotherapy Response in LUAD.

Shuai Zhao, Han Zhang, Qiuqiao Mu, Yuhang Jiang, Xiaojiang Zhao, Kai Wang, Ying Shi, Xin Li, Daqiang Sun.

  Background: Lung adenocarcinoma (LUAD) exhibits pronounced cellular and molecular heterogeneity that shapes tumor progression and therapeutic response. Although nucleotide metabolism is essential for sustaining tumor proliferation and coordinating immune interactions, its single-cell heterogeneity and clinical implications remain incompletely defined. Methods: We integrated a publicly available scRNA-seq dataset derived from independent LUAD patients to construct a comprehensive LUAD cellular atlas, identified malignant epithelial cells using inferCNV, and reconstructed differentiation trajectories via Monocle2. Cell-cell communication patterns under distinct nucleotide metabolic states were assessed using CellChat. A nucleotide metabolism-related signature (NMRS) was subsequently developed across TCGA-LUAD and multiple GEO cohorts using 101 combinations of machine learning algorithms. Its prognostic and immunological predictive value was systematically evaluated. The functional relevance of the key gene ENO1 was further verified through pan-cancer analyses and in vitro experiments. Results: We identified substantial nucleotide metabolic heterogeneity within malignant epithelial cells, closely linked to elevated proliferative activity, glycolytic activation, and increased CNV burden. Pseudotime analysis showed that epithelial cells gradually acquire enhanced immune-modulatory and complement-related functions along their differentiation continuum. High-metabolism epithelial cells exhibited stronger outgoing communication-particularly via MIF, CDH5, and MHC-II pathways-highlighting their potential role in shaping an immunosuppressive microenvironment. The NMRS built from metabolism-related genes provided robust prognostic stratification across multiple cohorts and surpassed conventional clinical parameters. Immune profiling revealed that high-NMRS tumors displayed increased T-cell dysfunction, stronger exclusion, higher TIDE scores, and lower IPS, suggesting poorer responses to immune checkpoint blockade. ENO1, markedly upregulated in high-NMRS tumors and functioning as a risk factor in several cancer types, was experimentally shown to promote invasion in LUAD cell lines. Conclusions: This study delineates the profound impact of nucleotide metabolic reprogramming on epithelial cell states, immune ecology, and malignant evolution in LUAD. The NMRS provides a robust predictor of prognosis and immunotherapy response across cohorts, while ENO1 emerges as a pivotal metabolic-immune mediator and promising therapeutic target.

Keywords:  ENO1; LUAD; immunotherapy; machine learning; nucleotide; scRNA-seq

DOI:  https://doi.org/10.3390/cancers18010160
J Clin Med. 2026 Jan 02. pii: 349. [Epub ahead of print]15(1):

Inflammatory-Molecular Clusters as Predictors of Immunotherapy Response in Advanced Non-Small-Cell Lung Cancer.

Vlad Vornicu, Alina-Gabriela Negru, Razvan Constantin Vonica, Andrei Alexandru Cosma, Mihaela Maria Pasca-Fenesan, Anca Maria Cimpean.

  Background/Objectives: Immunotherapy has improved outcomes for selected patients with advanced non-small-cell lung cancer (NSCLC), yet the predictive value of individual biomarkers such as PD-L1 remains limited. Systemic inflammatory indices derived from routine blood tests may complement molecular and immunohistochemical features, offering a broader view of host-tumor immunobiology. Methods: We conducted a retrospective study of 298 patients with stage IIIB-IV NSCLC treated with immune checkpoint inhibitors (ICIs) at a tertiary oncology center between 2022 and 2024. Baseline neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and systemic immune-inflammation index (SII) were collected alongside PD-L1 expression and molecular alterations (EGFR, KRAS, ALK, TP53). Patients were stratified into inflammatory-molecular clusters integrating these parameters. Associations with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were evaluated using Kaplan-Meier and multivariate Cox analyses. Results: Four distinct inflammatory-molecular clusters demonstrated significantly different outcomes (p < 0.001). Patients with low NLR and high PD-L1 expression (Cluster A) showed the highest ORR (41%), longest median PFS (13.0 months), and OS (22.5 months). The EGFR/ALK-driven, inflammation-dominant cluster (Cluster C) exhibited poor response (ORR 7%) and shortest survival (PFS 4.3 months). High NLR (HR 2.12), PD-L1 < 1% (HR 1.91), and EGFR mutation (HR 2.36) independently predicted shorter PFS. A combined model incorporating NLR, PD-L1, and molecular status outperformed individual biomarkers (AUC 0.82). Conclusions: Integrating systemic inflammatory indices with PD-L1 expression and molecular alterations identifies clinically meaningful NSCLC subgroups with distinct immunotherapy outcomes. This multidimensional approach improves prediction of ICI response and may enhance real-world patient stratification, particularly in settings with limited access to extended molecular profiling.

Keywords:  EGFR/KRAS mutations; PD-L1 expression; immune checkpoint inhibitors (ICIs); immunotherapy outcomes; neutrophil-to-lymphocyte ratio (NLR); non-small-cell lung cancer (NSCLC); prognostic biomarkers; systemic inflammatory indices

DOI:  https://doi.org/10.3390/jcm15010349
Transl Lung Cancer Res. 2025 Dec 31. 14(12): 5243-5256

O-GlcNAcylation levels predict radiotherapy outcome in non-small cell lung cancer.

Xiaoliang Wang, Yujiao Ma, Ying Dong, Yanling Wang, Jupeng Yuan, Jinming Yu, Dawei Chen.

   Background: Limited evidence exists on the role of protein glycosylation, particularly O-GlcNAcylation (O-GlcNAc), in predicting radiotherapy (RT) response in non-small cell lung cancer (NSCLC). This study aimed to investigate O-GlcNAc expression, glucose metabolism indicators, and their associations with RT response and prognosis in NSCLC.
Methods: We conducted a retrospective cohort study of 216 NSCLC patients who underwent RT and positron emission tomography-computed tomography (PET-CT) imaging. O-GlcNAc expression in pretreatment primary tumor specimens was evaluated by immunohistochemistry (IHC), and patients were categorized into high- and low-expression groups. All patients were matched for age, sex, diagnosis, and pathological stage. Clinical features were reviewed, and multivariable logistic regression was applied to analyze associations between O-GlcNAc levels and clinical parameters. The conditional logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs). Kaplan-Meier analysis was performed to evaluate the prognostic impact of O-GlcNAc expression. Pretreatment blood glucose levels and primary tumor glucose uptake [maximum standardized uptake value (SUVmax)] from PET-CT were also assessed, and correlation analyses were conducted to determine their relationships with RT response and survival outcomes.
Results: Low O-GlcNAc expression was independently associated with poor RT response (P=0.005; OR =2.47; 95% CI: 1.32-4.64) and significantly predicted shorter progression-free survival (PFS; log-rank P=0.049) and overall survival (OS; log-rank P=0.008). In contrast, blood glucose levels (P=0.59) and primary tumor SUVmax (P=0.38) showed no association with RT response, and neither blood glucose nor SUVmax correlated with PFS; however, high SUVmax was predictive of shorter OS (log-rank P=0.03).
Conclusions: High O-GlcNAc expression was a predictor of favorable RT response and improved PFS and OS in NSCLC patients.

Keywords:  Non-small cell lung cancer (NSCLC); O-GlcNAcylation (O-GlcNAc); blood glucose; maximum standardized uptake value (SUVmax); radiotherapy (RT)

DOI:  https://doi.org/10.21037/tlcr-2025-998
Mol Carcinog. 2026 Jan 07.

Lung Cancer Cells Secrete Glutamine to Accumulate Tumor-Associated Macrophages.

Joshua P Reddy, Rebecca A Clague, Beatriz P Peixoto, Sara Bernstein, Emma E Lauth, Clara Y Takanohashi, Sophie C Kim, Hiromi I Wettersten.

  Tumor-associated macrophages (TAMs) are critical contributors to cancer progression and are often recruited by cancer cells to support a pro-tumorigenic microenvironment. Integrin αvβ3 is a known driver and marker of cancer stem-like properties, including tumor initiation, in various epithelial cancers. We have previously shown a positive correlation between αvβ3 expression and TAM infiltration across multiple tumor types; however, the mechanistic link remains undefined. Here, we demonstrated that integrin αvβ3 expression in non-small cell lung cancer (NSCLC) cells is both necessary and sufficient to drive TAM accumulation. In orthotopic murine and human NSCLC models, ectopic integrin αvβ3 expression increased TAM infiltration independently of T cells, whereas genetic deletion of integrin β3 significantly reduced TAM numbers and tumor burden. Mechanistically, integrin αvβ3 promotes glutamine secretion from NSCLC cells, which enhances the survival and/or differentiation of bone marrow-derived macrophages. Functionally, TAMs are essential for the elevated tumor-initiating capacity of αvβ3+ cancer cells, as macrophage depletion abolished this effect. Together, our findings uncover a novel mechanism by which NSCLC cells remodel the tumor microenvironment via αvβ3-mediated glutamine secretion, promoting TAM enrichment and tumor initiation. Targeting this axis may offer therapeutic benefits in αvβ3-expressing cancers.

Keywords:  cancer metabolism; integrin αvβ3; non‐small cell lung cancer

DOI:  https://doi.org/10.1002/mc.70077
Discov Oncol. 2026 Jan 09.

MiR-31 suppresses lung adenocarcinoma cell proliferation through CDK1 and E2F2-mediated cell cycle arrest.

Pan Sun, Man Zhang, Shanshan Wang, Yulin He, Chenjing Lin, Yi Tian, Jizhuang Luo, Kai Wang.

   BACKGROUND: MicroRNAs (miRNAs) exert pivotal regulatory functions in cancer initiation, progression, and metastasis by regulating cell proliferation-cycle related genes. However, tumor-associated miRNAs in lung adenocarcinoma (LUAD) remains incompletely characterized.
RESULTS AND FINDINGS: By interrogating TCGA mRNA-Seq datasets, we identified 1672 differentially expressed genes (DEGs) implicated in proliferation-cycle regulation in LUAD. A significant overrepresentation of transmembrane signal receptors, kinases, and TFs was observed among the DEGs, with primary enrichment in signaling pathways such as chemokine/cytokine, Wnt, EGF, Cadherin, and p53 cascades. Remarkably, CDK1 and E2F2 were characterized as key proliferation-cycle regulatory genes, demonstrating > fivefold transcriptional up-regulation in LUAD specimens compared to normal lung tissues (p < 0.001). Mechanistically, pharmacological CDK1 inhibition using fostamatinib or alsterpaullone reversed aberrant proliferative phenotypes in LUAD cells, demonstrating therapeutic reversibility in vitro. Concurrently, DEmiRNA and target analysis identified miR-31 as a critical regulator of CDK1/E2F2, showing elevated expression in LUAD.
CLINICAL IMPLICATIONS: Collectively, our study establishes miR-31 as a novel biomarker for LUAD proliferative potential and implicates the miR-31/CDK1-E2F2 network as a promising target for disrupting LUAD progression. These findings establish a miRNA-centric precision therapeutic paradigm for effectively suppressing oncogenic proliferation in LUAD.

Keywords:  CDK1; Cell proliferation; E2F2; Lung adenocarcinoma (LUAD); miR-31

DOI:  https://doi.org/10.1007/s12672-025-04362-6
bioRxiv. 2025 Dec 25. pii: 2025.12.22.696060. [Epub ahead of print]

PDK1 and YAP1/TEAD signaling drive acquired KRAS inhibitor resistance in KRAS-mutant non-small cell lung cancer.

Amrita Barua, Samrat T Kundu, Sofia G Garza, Jared J Fradette, Bhagya Shree Choudhary, David H Peng, Lixia Diao, Jing Wang, Don L Gibbons.

Mutations in KRAS are responsible for driving approximately 30% of NSCLC. While historically considered undruggable, recent breakthroughs have seen the FDA approval of two potent KRAS G12C inhibitors, sotorasib (AMG510) and adagrasib (MRTX849). However, the efficacy of these inhibitors in the clinics has been limited by primary and acquired means of resistance. To elucidate mechanisms of acquired resistance, we generated a panel of resistant cell lines to the allele-specific KRAS inhibitors MRTX849 and MRTX1133 and observed an increased activation of the PDK1 and YAP1/TEAD signaling pathways. Pharmacological inhibition and genetic loss-of-function studies revealed a strong dependence on these pathways for the generation and maintenance of resistance to KRAS inhibition, which was then validated in vitro and in vivo . Furthermore, overexpression studies revealed that forced expression of either PDK1 or YAP1 led to increased resistance to KRAS inhibition in the sensitive lines. Taken together, our findings suggest that co-targeting PDK1 or YAP1/TEAD might be a potential approach to overcoming resistance to KRAS inhibition in NSCLC.

DOI: https://doi.org/10.64898/2025.12.22.696060