bims-meract Biomed News
on Metabolic reprogramming and anti-cancer therapy
Issue of 2026–07–26
twelve papers selected by
Andrea Morandi, Università degli Studi di Firenze
  1. Protein SUMOylation confers sorafenib resistance in human hepatocellular carcinoma via the induction of PKM2-mediated glycolysis.
  2. LSD1-GLS2 axis drives subtype-specific chemoresistance in pancreatic cancer through glutaminolysis reprogramming.
  3. Mitochondrial metabolism determines chemotherapy sensitivity in colorectal cancer.
  4. LARS Inhibition Overcomes Regorafenib Resistance in Hepatocellular Carcinoma via Ferroptosis and Drug Metabolism.
  5. FABP4 interacts with PPARγ to promote malignant progression in pancreatic cancer.
  6. Dynamic regulation of lysine and arginine metabolism promotes immune evasion by limiting T cell function in cancer.
  7. TOMM40/FADS2 Expression Ratio Predicts the Sensitivity to mTOR Inhibitors in Triple-Negative Breast Cancer.
  8. Targeting the mevalonate pathway sensitizes multiple myeloma cells to bortezomib through induction of mitochondrial metabolic disruption.
  9. IGSF3 drives acquired temozolomide resistance in glioblastoma through ASNS-dependent asparagine biosynthesis.
  10. Epiproteomic profiling identifies histone H4 hyperacetylation as a prognostic marker in pleural mesothelioma.
  11. Chemotherapy-induced senescence promotes stroma stiffness and antioxidant adaptation to promote chemoresistance in pancreatic ductal adenocarcinoma.
  12. RON receptor tyrosine kinase regulates abiraterone resistance in prostate cancer via the methylation-dependent and independent dual functions of DNMT1.
  1. Drug Resist Updat. 2026 Sep;pii: S1368-7646(26)00102-0. [Epub ahead of print]88 101451
    Protein SUMOylation confers sorafenib resistance in human hepatocellular carcinoma via the induction of PKM2-mediated glycolysis.
    Hongchao Yuan, Yuanjun Lu, Zhuofeng Jiang, Yau-Tuen Chan, Junyu Wu, Zixin Feng, Lin Xu, Qiucheng Li, Pengde Lu, Chun-Fung Kwok, Tung-Leong Fong, Qinguo Huang, Liuya Wei, Yibin Feng, Zhe-Sheng Chen, Ning Wang.
      Sorafenib resistance remains a major challenge in the treatment of hepatocellular carcinoma (HCC). Through an in vivo CRISPR/Cas9 screen, we identified protein SUMOylation as a key pathway enriched in sorafenib-resistant HCC tumors. SUMO1 expression was significantly upregulated in resistant tumors and cell lines, and its modulation directly influenced sorafenib sensitivity both in vitro and in vivo. Proteomic analysis revealed that SUMO1 overexpression enhanced glycolysis, and metabolic assays confirmed increased extracellular acidification rate (ECAR) and decreased oxygen consumption rate (OCR) in SUMO1-high cells. We further identified PKM2 as a key SUMOylation target, mediated by the E3 ligase TRIM28. The SUMOylation of PKM2 increased its enzymatic activity, promoted aerobic glycolysis, and conferred sorafenib resistance. The inhibition of PKM2 with Compound 3k reversed glycolytic flux and restored sorafenib sensitivity. Clinically, SUMOylated PKM2 was highly expressed in HCC tumors and was associated with the expression of markers of glycolysis and sorafenib resistance in HCC. Our study revealed a novel SUMO1-PKM2 axis that drives glycolysis and sorafenib resistance in HCC, suggesting a potential therapeutic target for overcoming drug resistance.
    Keywords:  Glycolysis; Hepatocellular carcinoma; PKM2; SUMO1; Sorafenib resistance
    DOI:  https://doi.org/10.1016/j.drup.2026.101451
  2. Cell Death Dis. 2026 Jul 20. pii: 649. [Epub ahead of print]17(1):
    LSD1-GLS2 axis drives subtype-specific chemoresistance in pancreatic cancer through glutaminolysis reprogramming.
    Zhefang Wang, Qiu Huang, Jiangang Zhao, Zicheng Lyu, Feng Ju, Bo You, Jie Wang, Qiongzhu Dong, Margarete Odenthal, Alexander Quaas, Kalliope N Diakopoulos, Hana Algül, Maximilian Reichert, Christiane J Bruns, Yue Zhao.
      Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy due to its aggressive biology and therapeutic resistance. Lysine-specific demethylase 1 (LSD1), an epigenetic regulator, is overexpressed in PDAC and linked to poor prognosis, yet its context-dependent roles in metabolic subtypes and chemoresistance remain undefined. Here, we show that LSD1 knockdown has opposing, subtype-specific effects on chemotherapeutic responses: it sensitized RSK-subtype cells (L3.6pl, PANC-1) to chemotherapy but induced resistance in KRAS-subtype cells (BxPC-3, TBO368). Integrated analyses revealed mitochondrial dysfunction and defective mitophagy as hallmarks distinguishing KRAS- from RSK-subtype PDAC. Critically, mitochondrial targeting through respiratory modulation or mitophagy manipulation overrides LSD1-mediated subtype-specific chemoresistance, establishing mitochondrial fitness as the mechanistic determinant. Mechanistically, LSD1 transcriptionally regulates GLS2 to drive glutamine metabolic reprogramming, promoting reductive carboxylation in KRAS-subtype cells and oxidative metabolism in RSK-subtype cells. Our work establishes the LSD1-GLS2 axis as a metabolic switch controlling PDAC chemosensitivity and provides a framework for subtype-specific therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41419-026-09075-4
  3. Nat Metab. 2026 Jul 23.
    Mitochondrial metabolism determines chemotherapy sensitivity in colorectal cancer.
    Deborah Y Moss, Connor N Brown, Andrew M Shaw, Christopher McCann, Nikita Lewis, Matilda Downs, Rebecca Wurelly, Ciara Cunningham, Aaron Philips, Niamh Doherty, Sarah Gallagher, William J McDaid, Andrew Roe, Aisling Y Coughlan, Brenton Cavanagh, Callum Ormsby, Fiammetta Falcone, Rachel McCole, Scott Monteith, Emily Rogan, Sudhir B Malla, Alexandra J Emerson, Letitia Mohammed-Smith, Shaun Sharkey, Aoife Leonard, Peter F Gallagher, Arindam Banerjee, Sandra Van Schaeybroeck, Sufyan Pandor, Brian Quinn, Brett Greer, Christopher Elliott, Sarah Maguire, Aideen E Ryan, Philip D Dunne, Mary Mallon, Stephanie Craig, Omar Aftab, Laura C Greaves, Bryan P Marzullo, Daniel A Tennant, Vicky Coyle, Ian G Mills, Owen Sansom, Tríona Ní Chonghaile, Daniel B Longley, Simon S McDade, Melissa J LaBonte, Emma M Kerr.
      Therapy resistance is attributed to over 80% of cancer deaths per year, emphasizing the urgent need to overcome this challenge for improved patient outcomes. Despite its widespread use in colorectal cancer (CRC) treatment, resistance to 5-fluorouracil (5FU) remains poorly understood. As an antimetabolite, 5FU imposes substantial metabolic stress, forcing cells that survive treatment to rapidly adapt. We explored acute 5FU-driven changes in mitochondria, the organelle critical for coordinating metabolic stress responses. Here we demonstrate in a range of CRC models that 5FU treatment promotes mitochondrial biogenesis and increases mitochondrial function in surviving cells. Furthermore, we show that targeting mitochondrial metabolism, particularly by inhibiting Complex I, sensitizes CRC cells to 5FU, resulting in delayed tumour growth and prolonged survival in preclinical models. Additionally, analysis of patient data suggests that oxidative metabolism signatures may predict responses to 5FU-based chemotherapy. These findings shed light on mechanisms underlying 5FU resistance and propose a rational strategy for combination therapy in CRC, emphasizing the potential clinical benefit of targeting mitochondrial metabolism to overcome resistance and enhance patient outcomes.
    DOI:  https://doi.org/10.1038/s42255-026-01578-w
  4. Eur J Pharm Sci. 2026 Jul 20. pii: S0928-0987(26)00188-0. [Epub ahead of print] 107614
    LARS Inhibition Overcomes Regorafenib Resistance in Hepatocellular Carcinoma via Ferroptosis and Drug Metabolism.
    Tung-Yao Tsai, Hsuan-Hwai Lin, Yi-Chiao Cheng, Vijesh Kumar Yadav, Chun-Chen Ko, Yih-Giun Cherng, Shiue-Wei Lai.
       BACKGROUND: Regorafenib improves outcomes in advanced hepatocellular carcinoma (HCC), but acquired resistance limits its durable therapeutic benefit. The metabolic and redox mechanisms driving regorafenib resistance remain incompletely defined.
    METHODS: Regorafenib-resistant Huh7 and Hep3B cell (RegR-) models were generated by long-term stepwise drug exposure. Transcriptomic profiling, LC-MS/MS, Seahorse extracellular flux analysis, ferroptosis-related assays, and apoptosis assays were used to characterize resistance-associated alterations. LARS1 was modulated by shRNA knockdown, overexpression, and pharmacological inhibition using BC-LI-0186. Therapeutic efficacy was evaluated in vitro and in Regᴿ Huh7 xenografts. Clinical relevance was assessed using paired HCC specimens, clinicopathological analysis, TCGA-LIHC, and TNMplot datasets.
    RESULTS: Regᴿ HCC cells showed increased regorafenib IC₅₀ values, retained migratory, invasive, clonogenic, and spheroid-forming capacity under regorafenib exposure, and exhibited extensive transcriptomic remodeling. Differential expression analysis identified 200 DEGs in Regᴿ Huh7 cells and 1,635 DEGs in Regᴿ Hep3B cells, with LARS1 and GPX4 among the upregulated candidates. Regᴿ cells displayed enhanced regorafenib glucuronidation, with approximately 2.3-fold and 2.7-fold higher glucuronide accumulation in Huh7 and Hep3B models, respectively. LARS1 expression positively correlated with the regorafenib-glucuronide/regorafenib ratio. Clinically, LARS1 and GPX4 were upregulated in HCC tissues and associated with aggressive clinicopathological features. LARS1 knockdown or BC-LI-0186 reduced regorafenib IC50, suppressed GPX4/SLC7A11 expression, increased lipid ROS and apoptosis, and disrupted the hypermetabolic phenotype of Regᴿ cells by reducing both OCR and ECAR. In xenograft models, combined regorafenib and BC-LI-0186 treatment produced the strongest tumor growth inhibition and reduced LARS1/GPX4 expression, although body-weight monitoring indicated the need for toxicity evaluation.
    CONCLUSIONS: LARS1 acts as a druggable metabolic regulator that links regorafenib biotransformation, mTOR-related metabolic adaptation, and GPX4/SLC7A11-mediated ferroptosis defense in resistant HCC. Targeting LARS1 with BC-LI-0186 may restore regorafenib sensitivity and represents a potential strategy for overcoming acquired regorafenib resistance.
    Keywords:  drug metabolism; ferroptosis; hepatocellular carcinoma; leucyl-tRNA synthetase; regorafenib resistance
    DOI:  https://doi.org/10.1016/j.ejps.2026.107614
  5. iScience. 2026 Jul 17. 29(7): 116547
    FABP4 interacts with PPARγ to promote malignant progression in pancreatic cancer.
    Chen-Xi Yang, Cun-Xia Li, Qian Zhang, Jing Yun, Hui Wang, Jian Huangfu, Jian-Jun Ren, Rui Xiao.
      Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with an exceptionally poor prognosis. Fatty acid-binding protein 4 (FABP4) has been implicated in tumorigenesis and peroxisome proliferator-activated receptor γ (PPARγ) signaling, but its precise functional role and underlying molecular mechanisms in PDAC remain poorly defined. Here, we showed that FABP4 is markedly upregulated in pancreatic cancer cells. Co-immunoprecipitation assays revealed an interaction between FABP4 and PPARγ, and FABP4 overexpression significantly enhanced pancreatic cancer cell viability, proliferation, and migratory capacity in vitro. Moreover, FABP4 overexpression was associated with increased lipid metabolic activity and reduced sensitivity to ferroptosis, and it substantially promoted the tumorigenic potential of PANC-1 cells in vivo. Notably, pharmacological inhibition of PPARγ effectively attenuated the malignant phenotypes elicited by FABP4 overexpression in pancreatic cancer cells, underscoring that PPARγ is critically involved in the FABP4-associated tumor progression phenotype.
    Keywords:  FABP4; PPARγ; fatty acid-binding protein 4; lipid metabolism; pancreatic ductal adenocarcinoma; peroxisome proliferator-activated receptor gamma
    DOI:  https://doi.org/10.1016/j.isci.2026.116547
  6. Sci Immunol. 2026 Jul 24. 11(121): eaeb7315
    Dynamic regulation of lysine and arginine metabolism promotes immune evasion by limiting T cell function in cancer.
    Weiwei Yu, Ruya Sun, Xiaoyang Lu, Qiqi Deng, Heng Zhang, Sheng Chen, Siqi Dai, Tianyi Hu, Xiangyuan Li, Yidong Yang, Lihao Chen, Zhexu Chi, Jian Zhang, Siwen Zhang, Yiyi Zhu, Dehang Yang, Qianzhou Yu, Zhen Wang, Quanquan Wang, Fan Yang, Qian Xiao, Kefeng Ding, Di Wang.
      Tumor cells promote metabolic dysregulation of immune cells by controlling the metabolic landscape of the tumor microenvironment. It is unclear whether tumors restrict specific nutrients to drive rapid growth and immune evasion in addition to the overconsumption of nutrients to support anabolism. We identified that up-regulation of solute carrier family 7 member 1 (SLC7A1) increased arginine utilization and promoted tumor growth, whereas down-regulation of SLC7A2 decreased lysine catabolism to support immune evasion. Repression of lysine catabolism in tumor cells reduced glutaconic acid (GC), a medium-chain acyl-CoA dehydrogenase-dependent lysine catabolite that has immunostimulatory effects on antitumor CD8 T cells. GC modified pyruvate kinase M2 (PKM2) through posttranslational glutaconylation at key lysine residues Lys336 (K336) and K337. This modification reinforced PKM2 dimers, transcriptionally driving metabolic reprogramming and reinvigorating antitumor CD8 T cells. Our study highlights an amino acid trade-off that dynamically optimizes the metabolic preferences of tumors to promote proliferation and immune evasion.
    DOI:  https://doi.org/10.1126/sciimmunol.aeb7315
  7. Cancer Med. 2026 Jul;15(7): e72089
    TOMM40/FADS2 Expression Ratio Predicts the Sensitivity to mTOR Inhibitors in Triple-Negative Breast Cancer.
    Salman Mohamed Farah, Jing-Quan Zheng, Leon Tsung-Ju Lee, Hsiao-Wei Lu, Wen-Ke Wang, Chia-Hao Kuei, Hui-Yu Lin, Hui-Wen Chiu, Yuan-Feng Lin.
       BACKGROUND: Triple-negative breast cancer (TNBC) is a subtype of breast cancer that lacks the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2). There is a lack of predictive biomarkers for the response of patients with TNBC to targeted therapies.
    METHODS: Bioinformatics analysis was conducted to generate differentially expressed genes (DEGs) of the mammalian target of rapamycin complex 1 (MTORC1) gene set between normal tissues and primary tumors derived from TNBC patients using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Cox regression analysis was performed to identify independent prognostic factors. Endogenous expression levels of the identified prognostic genes were detected in a panel of TNBC cell lines and breast cancer tissues using western blotting and immunohistochemistry (IHC).
    RESULTS: Our findings revealed two prognostic genes: FADS2 and TOMM40. TOMM40 (HR = 2.243) was a risk factor and FADS2 was a protective factor (HR = 0.652). A higher TOMM40/FADS2 ratio is associated with poor outcomes in patients with TNBC. The TOMM40/FADS2 ratio was significantly (p < 0.05) associated with age, tumor size, lymph node metastasis, pathologic stage, and overall survival of patients with TNBC. Remarkably, the MTT cytotoxicity assay revealed that TNBC cells, which possess a higher TOMM40/FADS2 ratio than TNBC cells with a lower TOMM40/FADS2 ratio, are more sensitive to mammalian target of rapamycin (mTOR) inhibitor treatment.
    CONCLUSION: Our results provide a new therapeutic strategy using the TOMM40/FADS2 expression ratio to predict the cellular sensitivity to mTOR inhibitor treatment in TNBC.
    Keywords:  FADS2; TOMM40; mTOR inhibitor; mTORC1; triple–negative breast cancer
    DOI:  https://doi.org/10.1002/cam4.72089
  8. Cell Commun Signal. 2026 Jul 20.
    Targeting the mevalonate pathway sensitizes multiple myeloma cells to bortezomib through induction of mitochondrial metabolic disruption.
    Shuya Li, Na Hu, Xiaodong Li, Yuan Feng, Yunmeng Ran, Zhipeng Geng, Hua Wang, Jinheng Wang.
       BACKGROUND: Multiple myeloma (MM) remains an incurable hematologic malignancy with bortezomib resistance representing a major therapeutic challenge. The mevalonate (MVA) pathway, a crucial metabolic cascade involved in cholesterol synthesis, has emerged as a potential target for cancer therapy.
    METHODS: In this study, we first investigated the correlations between the MVA pathway and MM progression. Leveraging public databases, transcriptome sequencing, mass cytometry, as well as in vitro and in vivo experimental models, we further systematically evaluated the therapeutic efficacy and underlying mechanisms of statins, a class of clinically available MVA pathway inhibitors, for the treatment of MM.
    RESULTS: Using microarray and sequencing datasets, we found that the MVA pathway is dysregulated in MM and correlated with poor prognosis, as core genes in this pathway were significantly dysregulated in MM patients. Statins directly inhibit MM cell viability, induce apoptosis, and up-regulate apoptosis-associated proteins. These effects of statins are associated with the activation of the ERK pathway. They also induce dysregulation of metabolism, oxidative stress, and autophagy in MM cells. Moreover, the combination of statins and bortezomib exerts a synergistic anti-MM effect both in vitro and in vivo.
    CONCLUSIONS: Our preclinical data suggest that the MVA pathway can serve as a therapeutic target for MM and the combination of statins, widely used and safe drugs in the clinic, with bortezomib offers a promising strategy to overcome bortezomib resistance and improve therapeutic outcomes for MM patients.
    Keywords:  Drug resistance; Multiple myeloma; Statins; The mevalonate pathway
    DOI:  https://doi.org/10.1186/s12964-026-03076-8
  9. J Biol Chem. 2026 Jul 22. pii: S0021-9258(26)02231-3. [Epub ahead of print] 113359
    IGSF3 drives acquired temozolomide resistance in glioblastoma through ASNS-dependent asparagine biosynthesis.
    Jie Li, Hongnian Lu, Qianqian Xu, Ying Yin, Zhening Pu, Jin Huang, Jingjing Wang.
      Glioblastoma (GBM) is the most aggressive primary malignancy of the central nervous system, and acquired resistance to temozolomide (TMZ) is a major cause of tumor recurrence and poor clinical outcome. However, the tumor-intrinsic drivers and metabolic adaptations underlying this process remain incompletely understood. In this study, we integrated transcriptomic data from established TMZ-sensitive and TMZ-resistant models with public bulk and single-nucleus sequencing datasets, and validated candidate genes using clinical specimens, cell-based drug-sensitivity assays, xenograft models, metabolic measurements, luciferase reporter assays, chromatin immunoprecipitation, and small-molecule binding assays. Immunoglobulin superfamily member 3 (IGSF3) was consistently upregulated in TMZ-resistant cells, resistant xenografts, and recurrent GBM samples, and was mainly enriched in malignant glioma cells. Functionally, IGSF3 overexpression promoted resistance to TMZ-related treatment, whereas IGSF3 knockdown restored drug sensitivity. Mechanistically, IGSF3 was detected in the nucleus, where it enhanced the activity of the asparagine synthetase (ASNS) promoter. Additionally, IGSF3 was found to be enriched at the ASNS promoter, thereby increasing ASNS expression and asparagine production, reduced reactive oxygen species accumulation, preserved glutathione redox balance, and limited DNA damage induced by treatment. ASNS gain- and loss-of-function rescue experiments showed that ASNS was required for the pro-resistance effect of IGSF3. Finally, Tucatinib bound to IGSF3, suppressed the IGSF3-ASNS pathway, and enhanced TMZ efficacy in vitro and in vivo. These findings identify the IGSF3-ASNS axis as a tumor-intrinsic metabolic adaptation that drives acquired TMZ resistance in GBM and suggest a potential therapeutic strategy for recurrent GBM.
    Keywords:  ASNS; Asparagine; Glioblastoma; IGSF3; TMZ resistance
    DOI:  https://doi.org/10.1016/j.jbc.2026.113359
  10. Lung Cancer. 2026 Jul 19. pii: S0169-5002(26)00605-7. [Epub ahead of print]219 109544
    Epiproteomic profiling identifies histone H4 hyperacetylation as a prognostic marker in pleural mesothelioma.
    Roberta Noberini, Ioanna Bischinioti, Simone Zanetti, Alessandro Vai, Giulia Sedda, Eltjona Mane, Claudia Bardoni, Giulia Robusti, Marianna D'Ercole, Rosanna Mancari, Ugo Cavallaro, Nicoletta Colombo, Luca Bertolaccini, Mariano Lombardi, Nicola Fusco, Lorenzo Spaggiari, Domenico Galetta, Tiziana Bonaldi.
      Pleural mesothelioma (PM) is an aggressive tumor that arises from mesothelial cells as a consequence of asbestos exposure. Despite recent therapeutic advances, the prognosis of PM remains poor, with a median overall survival typically below 18 months. Here, we investigated the association between alterations in histone post-translational modifications (PTMs) and patient survival in PM by employing state-of-the-art mass spectrometry-based epiproteomics. We profiled a cohort of 96 primary tumors obtained at diagnosis, including a subset of 25 patients with matched pre- and post-neoadjuvant treatment samples. Patients were stratified by overall survival using a 15-month cutoff, which approximates the reported median survival for PM. Several PTMs in treatment-naïve tumors, as well as a few therapy-induced changes, showed significant differences between short- and long-survivors across the different patient groups. Hyper-acetylation of the histone H4 tail at basal level was significantly and consistently increased in patients with worse prognosis, both in the entire cohort and within individual groups, and was associated with worse overall survival in Kaplan-Meier analyses. This association was independent of established clinicopathological variables in multivariable Cox regression models. Interestingly, increased histone H4 hyperacetylation was observed across multiple tumor types, supporting its broader relevance in cancer biology. In vitro, inhibition of histone acetyltransferases reduced PM cell viability and enhanced sensitivity to cisplatin in a synergistic manner. These findings identify histone H4 hyperacetylation as an independent prognostic biomarker in PM and highlight epigenetic modulation as a potential therapeutic avenue in PM.
    Keywords:  Epigenetics; Epiproteomics; Histone acetylation; Histone post-translational modification; Mass spectrometry; Pleural mesothelioma
    DOI:  https://doi.org/10.1016/j.lungcan.2026.109544
  11. Nat Commun. 2026 Jul 18.
    Chemotherapy-induced senescence promotes stroma stiffness and antioxidant adaptation to promote chemoresistance in pancreatic ductal adenocarcinoma.
    Xinxin Liu, Zhihua Huang, Bohan Yang, Yimeng Du, Yixin Sun, Enkui Zhang, Xiaofeng Kang, Chunyuan Xue, Kai Chen, Yongsu Ma, Xiaodong Tian, Xiaojie Xu, Yinmo Yang.
      Chemoresistance in pancreatic ductal adenocarcinoma (PDAC) is partly driven by pathological stromal remodeling, yet the underlying mechanisms remain poorly understood. Here, we show that gemcitabine treatment induces tumor cell senescence and activates cancer-associated fibroblasts via the senescence-associated secretory phenotype, leading to progressive fibrotic matrix stiffening. This biomechanical reprogramming engages the mechanosensitive ion channel Piezo1, triggering metabolic rewiring that renders BRG1-positive tumor cells increasingly dependent on NRF2-mediated antioxidant defenses. Piezo1 signaling promotes NRF2 nuclear translocation and its chromatin-remodeling cooperation with BRG1, thereby upregulating SLC7A11-dependent antioxidant programs and suppressing ferroptosis. Notably, the combination of the senolytic agent ABT-263 with the ferroptosis inducer Erastin effectively dismantles BRG1-NRF2-driven gemcitabine resistance, alleviates stromal fibrosis, enhances T-cell infiltration, and suppresses tumor growth in vivo. This senolytic-ferroptosis approach exploits metabolic vulnerabilities in chemotherapy-aged PDAC and provides a mechanistic rationale for stroma-targeted combination therapies.
    DOI:  https://doi.org/10.1038/s41467-026-75772-5
  12. Oncogene. 2026 Jul 24.
    RON receptor tyrosine kinase regulates abiraterone resistance in prostate cancer via the methylation-dependent and independent dual functions of DNMT1.
    Ke-Jie Wang, Kai-Yun Wang, Si-Xi Chen, Yu-Tao Ma, Rui Su, Yong-Bo Wang, Sha-Zhou Ye, Jun-Hui Jiang, Rui Yu, Ze-Jun Yan, Wei Chen, Qi Ma.
      Acquired resistance to the CYP17 inhibitor abiraterone is a critical challenge in the clinical treatment of metastatic prostate cancer; however, the mechanisms driving this resistance remain elusive. This study suggests that aberrant RON expression plays an important role in the development of acquired abiraterone resistance in prostate cancer cells. Increased RON expression was observed in most clinical tumor samples with an abiraterone-insensitive phenotype. In established prostate cancer cell lines, aberrant RON expression is associated with increased abiraterone resistance and enhanced migratory activity. These effects are mediated through dual regulatory functions of DNA methyltransferase 1(DNMT1): RON-mediated regulation of the canonical methyltransferase activity of DNMT1, which inhibits receptor-interacting protein kinase 3(RIPK3) expression, leading to increased cellular survival with impaired RIPK3/MLKL-involved cell death signaling. Concurrently, RON-driven non-methyltransferase activity of DNMT1 is associated with altered mitochondrial functions, thereby potentially enhancing cellular migration. The multi-kinase inhibitor BMS-777607, which has activity against RON, in combination with abiraterone suppressed both proliferation and metastasis in abiraterone-resistant xenograft tumors. The discovery of the RON-DNMT1-RIPK3 functional axis and the association between RON-DNMT1 and mitochondrial bioenergetic activity in this work strongly suggest RON as a critical driver of abiraterone resistance and a potential therapeutic target in prostate cancer.
    DOI:  https://doi.org/10.1038/s41388-026-03906-6
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