bims-meluca 2026-05-24 papers

Int J Biol Sci. 2026 ;22(9): 4618-4632

Canagliflozin and Brusatol Synergize against LKB1-KEAP1 Co-Mutant NSCLC through AKT Suppression.

Yiguan Chen, Xiang-Zheng Gao, Dade Rong, Liangliang Gao, Mingzhu Tang, Guang Lu, Zhi-Qiang Ling, Han-Ming Shen.

Liver kinase B1 (LKB1, encoded by STK11) is an important tumour suppressor, with approximately 30% of non-small cell lung cancer (NSCLC) patients harbouring LKB1 mutations. Our previous work showed that LKB1-mutant NSCLC cells are sensitive to glucose starvation, suggesting that suppression of glucose metabolism may serve as a potential therapeutic strategy for NSCLC patients with LKB1 mutation. In this study, we found LKB1 mutations frequently co-occur with mutations in Kelch-like ECH-associated-protein 1 (KEAP1), another key tumour suppressor regulating the NRF2-mediated antioxidant response. To target LKB1-KEAP1 co-mutant NSCLC, we utilized Canagliflozin, an FDA-approved sodium-glucose co-transporter 2 (SGLT2) inhibitor that mimics glucose starvation via inhibiting glucose uptake, in combination with Brusatol, an inhibitor of NRF2 signalling. Our results demonstrate that the combined treatment of Canagliflozin and Brusatol exerts potent anti-tumour effects in LKB1-KEAP1 co-mutant NSCLC cells both in vitro and in vivo. Mechanistically, the combination suppresses AKT activity and promotes AKT degradation, ultimately leading to apoptotic cell death. Taken together, these findings support the potential of combined Canagliflozin and Brusatol treatment as an effective therapeutic approach for LKB1-KEAP1 co-mutant NSCLCs.

Keywords: Brusatol; Canagliflozin; KEAP1; LKB1; NRF2; NSCLC

DOI: https://doi.org/10.7150/ijbs.124757

Oncogenesis. 2026 May 20.

Metabolic vulnerabilities in pleural mesothelioma.

Sílvia Plans-Marin, Cristina Muñoz-Pinedo, Ernest Nadal.

Mesothelioma is a rare tumour of mesothelial origin that is often diagnosed at advanced stages. Despite recent approval of immunotherapy, the prognosis of mesothelioma remains dismal. Growing evidence links tumour metabolism to the molecular mechanisms driving mesothelioma's aggressiveness, therapeutic resistance and poor outcomes. Mesothelioma-specific metabolic alterations may be derived from asbestos-induced chronic inflammation, the mesothelial origin, the pleural microenvironment and tumour-stroma interactions, as well as recurrent genomic alterations that distinguish mesothelioma from malignancies of the lung parenchyma. Elucidating these metabolic alterations is therefore crucial for identifying exploitable vulnerabilities and improving therapeutic strategies. Key metabolic pathways, including glycolysis, the pentose phosphate pathway, nucleotide biosynthesis and amino acid and lipid metabolism, are tightly interconnected within a dynamic network that regulates cell survival and proliferation. Metabolism also shapes tumour microenvironment by regulating redox homoeostasis, signalling and nutrient exchange. Considering these pathways in isolation provides an incomplete picture, and instead, studying them as a whole, and building a coherent metabolic map is essential for revealing context-specific dependencies. In this review, we summarise current knowledge of mesothelioma metabolism, highlighting how recurrent genetic alterations including CDKN2A, MTAP, BAP1, NF2 and TP53 influence metabolic phenotypes. We discuss experimental and therapeutic efforts that target individual metabolic branches and evaluate how these insights can inform a unified strategy to exploit metabolic weaknesses and guide the rational development of combination therapies.

DOI: https://doi.org/10.1038/s41389-026-00625-1

Mol Cancer. 2026 May 21.

Increased mRNA translation delays tumour initiation and exposes a therapeutic vulnerability in lung cancer.

BACKGROUND: Although inhibitors of mRNA translation are being evaluated as anti-cancer agents, the dynamics of protein synthesis throughout tumour progression are still poorly understood. Here we assess how alterations in mRNA translation during early tumorigenesis affect tumour development in KRAS-driven lung adenocarcinoma (LuAd).
METHODS: We deployed autochthonous mouse models of LuAd driven by oncogenic KRASG12D combined with moderate overexpression of MYC and simultaneously manipulated mRNA translation by deleting the mRNA helicases eIF4A1 and eIF4A2 or by administering pharmacological inhibitors of protein synthesis, such as rapamycin. This permits synchronous assessment of LuAd initiation and progression in vivo and is amenable to parallel ex vivo culture of tumour-derived cells for detailed analysis of protein synthesis (using ribosome footprinting) and metabolic landscapes. These approaches also allowed us to perform multiplex imaging and spatial transcriptomics to characterise tumour formation in altered mRNA translation conditions and to compare results obtained in mice against the Lattice-A cohort of non-small cell lung cancer (NSCLC) patients.
RESULTS: Deletion of the mRNA-translation repressor, eIF4A2 in KRAS-driven LuAd leads to a dysregulated protein synthesis landscape characterised by a strongly upregulated secretome, enlarged secretory compartments, increased oxidative metabolism and acquisition of senescence-like characteristics. Paradoxically, this overdriven secretory protein synthesis landscape delays tumorigenesis and leads to the appearance of clusters of non-proliferative, p21-positive KRASG12D-expressing cells in the lung. Consistently, reduction of mRNA translation with rapamycin in Eif4a2-deleted tumours suppresses senescence and restores tumorigenesis. Importantly, some Eif4a2 knockout cells overcome senescence to form tumours that exhibit enhanced MAP-kinase signalling and, in contrast to eIF4A2+/+ lesions, these were eradicated by administration of a MEK inhibitor. Consistently, MAP-kinase signalling was significantly increased in human NSCLC expressing low levels of eIF4A2.
CONCLUSIONS: Our study highlights that restraint of mRNA translation by eIF4A2 is critical in the early-stages of KRAS-driven LuAd to allow bypass of oncogene-induced senescence and tumour progression. Importantly, because tumours with dysregulated mRNA translation rely heavily on MAP-kinase signalling they are exquisitely sensitive to MEK inhibition, and this indicates the possibility that low expression of eIF4A2 could be used to identify potential responders to MEK inhibitors in clinical trials.

Keywords: KRAS; Lung adenocarcinoma; Metabolism; Oncogene-induced senescence; Rapamycin; Trametinib; eIF4A; mRNA translation

DOI: https://doi.org/10.1186/s12943-026-02680-z

Transl Lung Cancer Res. 2026 Apr 30. 15(4): 75

TLR7 induces autophagy in non-small cell lung cancer tumor cells and influences anti-tumors responses in patients.

Lucas Leonardi, Solenne Marmier, Nathalie Josseaume, Sophie Sibéril, Mathilde Prieto, Karen Leroy, Audrey Mansuet-Lupo, Diane Damotte, Marco Alifano, Isabelle Cremer, Pierre-Emmanuel Joubert.

Background: Autophagy is a fundamental catabolic process with context-dependent roles in cancer. In non-small cell lung cancer (NSCLC), its clinical significance and therapeutic implications remain unclear. Toll-like receptor 7 (TLR7) has been implicated in the modulation of tumor-immune interactions, but its connection to autophagy and treatment response has not been defined. Here, we aimed to investigate whether TLR7 signaling regulates autophagy in NSCLC and to determine its impact on tumor progression and therapeutic responses.
Methods: We combined transcriptomic analyses of multiple NSCLC patient cohorts with in vitro and ex vivo functional assays to investigate the relationship between TLR7 activation and autophagy. Gene expression profiling was used to assess the presence of TLR7 ligands and autophagy signatures in the tumor microenvironment (TME). Associations between tumor autophagy levels, clinical outcomes, and therapeutic responses were evaluated retrospectively in independent cohorts.
Results: Our analyses revealed that endogenous TLR7 ligands are present in the NSCLC TME, where they activate autophagy in malignant cells. High tumor TLR7-dependent autophagy was associated with poor prognosis and reduced sensitivity to platinum-based chemotherapy. Conversely, elevated autophagy correlated with improved responses to nivolumab, an anti-programmed death-1 (PD-1) immunotherapy. Mechanistic studies demonstrated that TLR7-induced autophagy promotes resistance to cisplatin (Cis.) and oxaliplatin (Oxali.) while upregulating PD-L1 expression, establishing a direct link between autophagy and therapeutic outcomes.
Conclusions: These findings identify TLR7-driven autophagy as a novel pathogenic pathway in NSCLC and a clinically relevant determinant of treatment response. This mechanism provides new insight into how tumor-intrinsic innate signaling shapes sensitivity to chemotherapy and immunotherapy, offering potential targets for therapeutic modulation.

Keywords: Autophagy; anti-programmed death-1 therapy (anti-PD-1 therapy); chemotherapy; toll like receptor

DOI: https://doi.org/10.21037/tlcr-2025-aw-1173