bims-meract 2025-08-03 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2025–08–03
ten papers selected by
Andrea Morandi, Università degli Studi di Firenze

De novo pyrimidine biosynthesis inhibition synergizes with BCL-XL targeting in pancreatic cancer.
Targeting AKR1B1 inhibits metabolic reprogramming to reverse systemic therapy resistance in hepatocellular carcinoma.
AGPAT4 targeted covalent inhibitor potentiates targeted therapy to overcome cancer cell plasticity in hepatocellular carcinoma mouse models.
High Co-Expression of GPAT4 and SLC7A11 as a Predictor of Platinum Resistance and Poor Prognosis in Patients with Epithelial Ovarian Cancer.
PNKP targeting engages the autophagic machinery through STING and STAT3 to potentiate ferroptosis and chemotherapy in TNBC.
Inhibition of the Caveolin-1 pathway promotes apoptosis and overcomes pan-tyrosine kinase inhibitor resistance in hepatocellular carcinoma.
Disrupting tRNA modifications to target mitochondrial vulnerabilities in drug-resistant leukemia cells.
Therapeutic targeting of syndecan-1 axis overcomes acquired resistance to KRAS-targeted therapy in gastrointestinal cancers.
TIGAR inhibits glucose-metabolism and cisplatin-chemosensitivity in human lung cancer cells.
Carbonic Anhydrase Inhibition Sensitizes Group 3 Medulloblastoma to Radiation Therapy.

Nat Commun. 2025 Jul 30. 16(1): 6987

De novo pyrimidine biosynthesis inhibition synergizes with BCL-XL targeting in pancreatic cancer.

Huan Zhang, Naiara Santana-Codina, Qijia Yu, Clara Poupault, Claudia Campos, Xingping Qin, Nicole Sindoni, Marina Ciscar, Aparna Padhye, Miljan Kuljanin, Junning Wang, Matthew J Dorman, Peter Bross, Andrew J Aguirre, Stephanie K Dougan, Kristopher A Sarosiek, Joseph D Mancias.

Oncogenic KRAS induces metabolic rewiring in pancreatic ductal adenocarcinoma (PDAC) characterized, in part, by dependency on de novo pyrimidine biosynthesis. Pharmacologic inhibition of dihydroorotate dehydrogenase (DHODH), an enzyme in the de novo pyrimidine synthesis pathway, delays pancreatic tumor growth; however, limited monotherapy efficacy suggests that compensatory pathways may drive resistance. Here, we use an integrated metabolomic, proteomic and in vitro and in vivo DHODH inhibitor-anchored genetic screening approach to identify compensatory pathways to DHODH inhibition (DHODHi) and targets for combination therapy strategies. We demonstrate that DHODHi alters the apoptotic regulatory proteome thereby enhancing sensitivity to inhibitors of the anti-apoptotic BCL2L1 (BCL-XL) protein. Co-targeting DHODH and BCL-XL synergistically induces apoptosis in PDAC cells and patient-derived organoids. The combination of DHODH inhibition with Brequinar and BCL-XL degradation by DT2216, a proteolysis targeting chimera (PROTAC), significantly inhibits PDAC tumor growth. These data define mechanisms of adaptation to DHODHi and support combination therapy targeting BCL-XL in PDAC.

DOI: https://doi.org/10.1038/s41467-025-61242-x
Signal Transduct Target Ther. 2025 Aug 01. 10(1): 244

Targeting AKR1B1 inhibits metabolic reprogramming to reverse systemic therapy resistance in hepatocellular carcinoma.

Qi Wang, Juan Liu, Ming Yang, Jun Zhou, Yaxuan Li, Jingjing Zheng, Hao Jia, Shuhua Yue, Yinpeng Le, Yuxin Su, Wenrui Ma, Ni An, Yunfang Wang, Jiahong Dong.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, and resistance to systemic therapies remains a significant clinical challenge. This study investigated the mechanisms by which metabolic reprogramming contributes to systemic treatment resistance in HCC. We established HCC cell lines with multidrug resistance characteristics and observed enhanced metabolic activity in these cells. Integrated multiomics analyses revealed hyperactive glucose‒lipid and glutathione metabolic pathways that play critical roles in supporting tumor cell proliferation and survival. We constructed a metabolic reprogramming atlas for HCC-resistant cells and identified aldo-keto reductase (Aldo-keto reductase family 1 Member B1, AKR1B1) as a key regulator of this reprogramming, which sustains drug resistance by regulating energy metabolism and enhancing stress tolerance. Importantly, AKR1B1 expression levels are closely associated with drug resistance and poor prognosis in HCC patients. The secretory nature of AKR1B1 not only underscores its predictive value but also facilitates the intercellular transmission of drug resistance. In terms of overcoming resistance, the AKR1B1 inhibitor epalrestat significantly mitigated drug resistance when it was used in combination with standard therapies. These findings underscore the importance of metabolic reprogramming in the development of HCC resistance. AKR1B1, a key enzyme that regulates metabolic reprogramming, has been identified as a potential biomarker and therapeutic target, providing new insights into overcoming resistance in HCC treatment.

DOI: https://doi.org/10.1038/s41392-025-02321-9
Sci Transl Med. 2025 Jul 30. 17(809): eadn9472

AGPAT4 targeted covalent inhibitor potentiates targeted therapy to overcome cancer cell plasticity in hepatocellular carcinoma mouse models.

Kai-Yu Ng, Tin-Yan Koo, Ianto Bosheng Huang, Terence Kin-Wah Lee, Tsz-Lok Fong, Ya Gao, Tin-Lok Wong, Yuan Gao, Jing-Ping Yun, Xin-Yuan Guan, Ming Liu, Clive Yik-Sham Chung, Stephanie Ma.

The development of cancerous cells leads to considerable changes in metabolic processes to meet the demands of tumor growth. Tumor lineage plasticity has been identified as a key factor in therapy resistance and tumor recurrence. Herein, we showed one aspect of this plasticity to be abnormal glycerophospholipid metabolism, specifically the presence of a metabolic protein called 1-acylglycerol-3-phosphate o-acyltransferase 4 (AGPAT4). We identified AGPAT4 as an oncofetal protein that is abundant in embryonic stem cells and hepatocellular carcinoma (HCC) tumor cells but is low or absent in most normal tissues. We demonstrated that AGPAT4 is a functional regulator of tumor lineage plasticity, which correlates with enhanced metastasis and resistance to sorafenib. Heightened plasticity was induced as a result of increased AGPAT4-mediated conversion of LPA (lysophosphatidic acid) to phosphatidic acid (PA), which then acts on its downstream mTOR/S6K/S6 signaling pathway. Inhibition of Agpat4 by the AAV8-mediated liver-directed strategy in an immunocompetent HCC mouse model reduced tumorigenicity and stemness and sensitized tumors to sorafenib. Through a chemical biology approach, a cysteine-reacting compound that specifically targets AGPAT4 at the Cys228 residue and therefore hinders its acyltransferase activity was identified and found to work synergistically with sorafenib in suppressing HCC in tumor xenograft models derived from patients with preclinical HCC and sorafenib-resistant HCC. Toxicological analysis revealed minimal side effects associated with the covalent inhibitor. In conclusion, the plasticity of tumor lineages induced by AGPAT4 represents a potential target for HCC treatment and could expand the effectiveness of sorafenib treatment, offering new possibilities for HCC therapy.

DOI: https://doi.org/10.1126/scitranslmed.adn9472
Biomedicines. 2025 Jul 08. pii: 1664. [Epub ahead of print]13(7):

High Co-Expression of GPAT4 and SLC7A11 as a Predictor of Platinum Resistance and Poor Prognosis in Patients with Epithelial Ovarian Cancer.

Ping Yu, Chunliang Shang, Zhongyu Liu, Yuan Li, Tianhui He, Yuan Xue, Jian Lin, Yuan Li, Yu Wu, Tong Liu, Hongyan Guo.

  Background/Objectives: This study aimed to determine whether the expression levels of GPAT4 and SLC7A11 are associated with survival outcomes and platinum resistance in epithelial ovarian cancer (EOC) patients. Methods: We analyzed the medical records of EOC patients. EOC samples obtained during surgery were stained for GPAT4 and SLC7A11. Cox regression and Kaplan-Meier analyses were performed to assess the impact of GPAT4 and SLC7A11 expression on overall survival (OS). Results: We found that GPAT4 and SLC7A11 expression levels were greater in platinum-resistant ovarian cancer tissues than in platinum-sensitive ovarian cancer tissues. High expression of both GPAT4 and SLC7A11 was associated with an increased risk of platinum resistance compared with low expression of both factors. High expression of both SLC7A11 and GPAT4 was independently correlated with poor OS, highlighting the significance of this integrated metric as a prognostic factor in ovarian cancer. The GPAT inhibitor (GPAT-IN-1) and an SLC7A11 inhibitor (erastin) attenuated platinum resistance in ovarian cancer cells, and their combined application increased cytotoxicity. Furthermore, the combination of GPAT-IN-1, erastin, and cisplatin significantly improved the chemotherapeutic effects on platinum-resistant ovarian cancer cells. Conclusions: High expression of both SLC7A11 and GPAT4 is related to platinum resistance in EOC patients. The high expression of both SLC7A11 and GPAT4 serves as an important independent prognostic factor and indicates potential therapeutic targets for patients with platinum-resistant EOC.

Keywords:  GPAT4; SLC7A11; ferroptosis; ovarian cancer; platinum resistance

DOI:  https://doi.org/10.3390/biomedicines13071664
Redox Biol. 2025 Jul 22. pii: S2213-2317(25)00288-5. [Epub ahead of print]86 103775

PNKP targeting engages the autophagic machinery through STING and STAT3 to potentiate ferroptosis and chemotherapy in TNBC.

Avi Maimon, Pier Giorgio Puzzovio, Yaron Vinik, Gavriel-David Hannuna, Sara Donzelli, Daniela Rutigliano, Giovanni Blandino, Sima Lev.

  The polynucleotide kinase/phosphatase (PNKP) is a DNA repair enzyme possessing bifunctional DNA 3'-phosphatase and DNA 5'-kinase activities. It plays an important role in the rejoining of single- and double-strand DNA breaks and is considered as a potential therapeutic target for different cancer types. Here we show that PNKP is highly expressed in triple negative breast cancer (TNBC) and associated with poor prognosis and chemoresistance. Targeting of PNKP enhanced ferroptosis in TNBC, which was associated with increased labile iron pool and ROS and concomitantly decreased in intracellular glutathione, SCD1 and GPX4 levels. Transcriptomic profiling and mechanistic data indicate that PNKP targeting robustly enhances the lysosomal and the autophagic machinery by activating STING and concurrently inhibiting STAT3, thereby increasing ferritinophagy, intracellular iron level and modulating the expression of key ferroptosis regulators. Importantly, PNKP and STAT3 are rapidly phosphorylated, colocalize, and interact upon ferroptosis induction or doxorubicin treatment, the first line treatment for TNBC patients. Targeting PNKP together with doxorubicin synergistically inhibited the growth of TNBC in an animal model and of TNBC-patients derived organoids. These results offer a promising therapeutic combination for TNBC and highlight the clinical potential of PNKP targeting and ferroptotic death for TNBC therapy.

Keywords:  Ferroptosis; PNKP; STAT3; STING; TNBC therapy

DOI:  https://doi.org/10.1016/j.redox.2025.103775
Cell Death Dis. 2025 Jul 25. 16(1): 561

Inhibition of the Caveolin-1 pathway promotes apoptosis and overcomes pan-tyrosine kinase inhibitor resistance in hepatocellular carcinoma.

Liver Cancer Collaborative

Resistance to multi-tyrosine kinase inhibitors (TKI) is a major clinical concern in advanced hepatocellular carcinoma (HCC). Herein, we aimed to uncover the mechanisms underlying pan-TKI resistance and to identify potential therapeutic targets. We used multiple TKI-resistant HCC cell lines to identify caveolin-1 (CAV1) as a key driver of therapeutic resistance. CAV1 downregulation induced apoptosis, inhibited metastasis and restored TKI sensitivity in both inherent and acquired TKI-resistant HCC cells. Mechanistically, in acquired TKI-resistant cells aberrant CAV1/STAT3/P70S6K signalling is required for their survival, motility, and invasiveness. CAV1 inhibition reduced expression of dormancy regulators E-cadherin, RAC1 and p21, enhanced cancer stemness markers, and disrupted downstream STAT3/P70S6K and AMPKα signalling pathways, prompting cancer cells to exit from dormancy and initiate autophagy-induced cell death. Furthermore, selective inhibition of AXL and FGFR4 downstream of the CAV1 pathway sensitized TKI-resistant cells to sorafenib and lenvatinib, respectively. In addition, microRNA-7-5p (miR-7) was identified as an endogenous regulator of CAV1; and miR-7's inhibitory effect on CAV1 and FGFR4 suppressed the STAT3/P70S6K pathway, promoted autophagy and triggered apoptosis in lenvatinib-resistant cells. Combination therapy using either lenvatinib or sorafenib and selective CAV1 inhibitors (e.g., siCAV1/miR-7), or AXL/FGFR4 inhibitors (e.g., BGB324/BLU9931) effectively overcame pan-TKI resistance. In HCC patient datasets, elevated CAV1 mRNA was observed in sorafenib non-responders, and single cell RNA-sequencing of HCC patient tumours revealed a rare population of CAV1+ cancer cells associated with recurrence. High CAV1 expression was specific to HBV+ HCC patients and independently predicted poor survival. Further, targeting of CAV1, AXL or FGFR4 effectively overcame TKI resistance in HCC patient derived organoids (PDOs). Our findings highlight a previously unrecognized role for CAV1-driven signalling in sustaining tumour dormancy, a critical and challenging therapeutic barrier underlying recurrence and pan-TKI resistance in HCC. Therapeutically targeting these pathways offer a promising and novel strategy to eliminate dormant tumour cells, thereby overcoming resistance and improving treatment outcomes.

DOI: https://doi.org/10.1038/s41419-025-07887-4
Blood. 2025 Aug 01. pii: blood.2024027822. [Epub ahead of print]

Disrupting tRNA modifications to target mitochondrial vulnerabilities in drug-resistant leukemia cells.

Cornelius Pauli, Michael Kienhöfer, Maximilian Felix Blank, Oguzhan Begik, Christian Rohde, Sarah Mn Zimmermann, Laura Werner, Daniel Heid, Fu Xu, Katharina Weidenauer, Sylvain Delaunay, Nadja Krall, Katrin Trunk, Duoduo Zhao, Fengbiao Zhou, Laia Llovera, Ollivier Alexane, Anke Heit-Mondrzyk, Uwe Platzbecker, Claudia D Baldus, Hubert Serve, Martin Bornhäuser, Cathrine B Vågbø, Salvador Aznar Benitah, Jeroen Krijgsveld, Eva Maria Novoa, Carsten Müller-Tidow, Michaela Frye.

Dysregulated RNA modifications contribute to cancer progression and therapy resistance, yet the underlying mechanism often remains unknown. Here, we perform CRISPR-based synthetic lethality screens to systematically explore the role of RNA modifications in mediating resistance to anti-leukaemic drugs. We identify the TRMT5-mediated formation of N1-methylguanosine (m1G) in the tRNA anticodon loop as essential for mediating drug tolerance to cytarabine and venetoclax in acute myeloid leukemia (AML). TRMT5 methylates nearly all mitochondrial and nuclear tRNAs with a guanosine at position 37, but its role in promoting drug tolerance specifically depends on its mitochondrial function. TRMT5 is essential for the dynamic upregulation of mitochondrial mRNA translation and oxidative phosphorylation (OXPHOS), which are critical for sustaining drug tolerance in leukemia cells. This mitochondrial dependency correlates with therapy outcomes in leukemia patients: lower expression of electron transport chain genes is linked to poorer outcomes in a cohort of nearly 100 AML patients undergoing first induction therapy. Finally, we demonstrate that targeted depletion of TRMT5 protein using a conditional degron, in conjunction with cytarabine and venetoclax treatment, synergistically induces cell death in drug-tolerant AML cells. Thus, our study reveals TRMT5 as promising drug target for therapy-resistant leukemia.

DOI: https://doi.org/10.1182/blood.2024027822
Cell Rep Med. 2025 Jul 22. pii: S2666-3791(25)00326-X. [Epub ahead of print] 102253

Therapeutic targeting of syndecan-1 axis overcomes acquired resistance to KRAS-targeted therapy in gastrointestinal cancers.

Madelaine S Theardy, Mitsunobu Takeda, Alexey Sorokin, Shuaitong Chen, Zecheng Yang, Xiaofei Wang, Preeti Kanikarla, Oluwadara Coker, Phuoc Nguyen, Yongkun Wei, Jun Yao, Liang Yan, Yanqing Jin, Yiming Cai, Masakatsu Paku, Ziheng Chen, Kara Z Li, Francesca Citron, Hideo Tomihara, Sisi Gao, Angela K Deem, Jun Zhao, Huamin Wang, Samir Hanash, Ronald A DePinho, Anirban Maitra, Giulio F Draetta, Haoqiang Ying, Scott Kopetz, Wantong Yao.

  The therapeutic benefit of recently developed mutant KRAS (KRAS∗) inhibitors remains limited by the rapid onset of resistance. Here, we aim to delineate mechanisms underlying acquired resistance and identify actionable targets for overcoming this clinical challenge. Previously, we identified syndecan-1 (SDC1) as a key effector for pancreatic cancer progression whose surface expression is driven by KRAS∗. By leveraging both pancreatic and colorectal cancer models, we show that surface SDC1 expression initially diminishes upon KRAS∗ inhibition but recovers in tumor cells that bypass KRAS∗ dependency. Mechanistically, we reveal that YAP1 activation drives the recovery of SDC1 surface localization to enhance macropinocytosis-mediated nutrient salvaging and activation of multiple receptor tyrosine kinases for tumor maintenance, promoting resistance to KRAS∗-targeted therapy. Overall, our study provides a strong rationale for targeting the YAP-SDC1 axis to overcome resistance to KRAS∗ inhibition, thereby revealing promising therapeutic opportunities for improving the clinical outcome of patients with KRAS∗-mutated cancers.

Keywords:  KRAS inhibitor; colorectal cancer; macropinocytosis; pancreatic cancer; syndecan; therapy resistance

DOI:  https://doi.org/10.1016/j.xcrm.2025.102253
Discov Oncol. 2025 Jul 28. 16(1): 1420

TIGAR inhibits glucose-metabolism and cisplatin-chemosensitivity in human lung cancer cells.

Yang Feng, Yiling Meng, Meichao Zhang, Yingxia Ying, Yuan Yao, Dong Li.

  TIGAR is an important factor associated with tumor glucose metabolism, but its function and underlying mechanism in human lung cancer remains unclear. Here, we analyzed the expression changes, prognosis, genetic alteration, related gene networks and metabolic pathways of TIGAR in lung cancer. The findings revealed that TIAGR level was augmented in LUAD and LUSC in comparison to the normal lung tissue. In addition, high TIAGR level was related to poorer outcome of patients with LUAD. Different alterations in TIGAR gene at various sites were observed in both LUAD and LUSC. The GO/KEGG analyses indicated that TIGAR affects the occurrence and progress of lung cancer through multiple metabolic pathways. Further, we established lung cancer cell models with TIGAR knockdown or overexpression to explore its effects on glucose metabolism, apoptosis and chemosensitivity. Our results indicated that TIGAR markedly inhibited glucose metabolism, ROS production, and susceptibility of lung cancer cells to cisplatin. Together, TIGAR plays a cancer-promoting role in lung cancer, which becomes a promising prognostic and therapeutic biomarker.

Keywords:  Bioinformatics; Chemosensitivity; Lung cancer; Metabolism; TIGAR

DOI:  https://doi.org/10.1007/s12672-025-03274-9
Cancer Res. 2025 Jul 25.

Carbonic Anhydrase Inhibition Sensitizes Group 3 Medulloblastoma to Radiation Therapy.

Cory M Richman, Alexandra Rasnitsyn, Borja L Holgado, Maria Vladoiu, Namal Abeysundara, Sandra Majo, Sara Chabi, Lucie J Taunay, Hiromichi Suzuki, Ichiyo Shibahara, Joonas Haapasalo, Jonelle G Pallotta, Tajana Douglas, Kaitlin Kharas, Kyle Juraschka, Oliver Ocsenas, Sachin A Kumar, Kristiina Nordfors, Ana Guerreiro Stücklin, Raul A Suarez, Jiao Zhang, Xiaochong Wu, Craig Daniels, Livia Garzia, Jüri Reimand, Olivier Saulnier, Thomas E Merchant, Celio Pouponnot, David R Raleigh, Michael D Taylor, Pasqualino De Antonellis.

Group 3 (G3) medulloblastoma constitutes the most aggressive molecular subgroup and nearly all patients present with metastases upon recurrence. Treatment for newly diagnosed medulloblastoma relies on a combination of maximal safe surgical resection followed by chemotherapy and ionizing radiation, and no therapies have been shown to confer a survival benefit at the time of recurrence. Given the limited therapeutic options available for patients with medulloblastoma, especially at recurrence, and the incomplete understanding of the molecular mechanisms underlying medulloblastoma resistance to treatment, we sought to uncover actionable targets and biomarkers that could help to refine patient selection and treatment of newly diagnosed medulloblastoma to reduce the risk of recurrence. In clinically relevant mouse models of G3 medulloblastoma, CT-guided fractionated radiotherapy extended overall survival and induced the clonal selection of radioresistant subpopulations of tumor cells that drove medulloblastoma recurrence. Comparison of recurrent tumors to treatment naïve newly diagnosed tumors revealed a gene expression signature that was found to be a biomarker of radioresistance and poor prognosis. This prognostic gene signature was shown to be subgroup specific in a large patient cohort. Recurrent tumors had elevated expression of carbonic anhydrase 4 (CA4), and genetic and pharmacological modulation of CA4 could promote or reduce resistance to radiotherapy. These data suggest that the FDA-approved carbonic anhydrase inhibitor acetazolamide may be a useful radiosensitizer to improve the efficacy of treatment of newly diagnosed G3 medulloblastoma that could reduce the risk of tumor recurrence and improve survival in pediatric patients.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-3894