bims-merabr 2026-03-01 papers

bims-merabr

Biomed News

on Metabolic rewiring in aggressive breast cancer

Issue of 2026–03–01
thirteen papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center

NAT10 Modulates Breast Cancer Progression Via Ac⁴C-Mediated Regulation of TRAF6 Expression and Glycolytic Metabolism.
Obesity and Tumor Development Reprogram the Proteome and Metabolic Effects of Adipose- and Tumor-Derived Extracellular Vesicles.
Targeting PFKFB3 to enhance CDK4/6 inhibitor response in ER+ breast cancer.
Hypoxia-induced LGALS8-AS1 sustains oxidative phosphorylation to drive breast cancer progression.
Reprogramming tumour-associated macrophages in breast cancer via si-FOXM1-loaded lipid nanoparticles enhances immune checkpoint inhibitor efficacy.
Evaluating Therapeutic Efficacy of SCL7A11 and GLUT1 Inhibition in Triple-Negative Breast Cancer via a GSH/ATP Dual-NIR-Responsive Fluorogenic Sensor.
Adipose Tissue Extracellular Matrix Remodeling: A Driver of Obesity and Insulin Resistance.
Mechanisms of HIF-1α Function in Malignant Cells and Associated Therapeutic Strategies.
Tumor microenvironment and key signaling pathways in breast cancer progression and therapy resistance: A review.
Silencing CD24 Inhibits Proliferation, Migration, and Chemoresistance in Triple-Negative Breast Cancer Cells.
Hypoxia-Responsive Retinoid Liposomes for Tumor Microenvironment-Activated Differentiation and Metastasis Suppression.
CRMP2 inhibits metastasis formation by impairing ILF3-dependent stabilization of CXCL10 mRNA in breast cancer.
Targeting PCK1 to overcome CDK4/6 inhibitor resistance for breast cancer therapy.

Mol Carcinog. 2026 Feb 23.

NAT10 Modulates Breast Cancer Progression Via Ac⁴C-Mediated Regulation of TRAF6 Expression and Glycolytic Metabolism.

Weiwei Bai, Meidi Zhu, Xiaochun Kan, Ye Zhang, Yingchun Zhang.

  NAT10, an essential enzyme catalyzing RNA ac⁴C modification, is recognized as a critical regulator of tumorigenesis and progression. This study investigates the role and underlying molecular mechanisms of NAT10 in breast cancer. We found that NAT10 is significantly overexpressed in breast cancer tissues compared to adjacent normal tissues, exhibiting high diagnostic accuracy (AUC = 0.9702, p < 0.001). Consistently, NAT10 expression was also elevated in breast cancer cell lines. Knockdown of NAT10 potently inhibited cell viability, glycolysis (as indicated by reduced glucose uptake, lactate production, and ECAR), and metastatic potential (manifested as suppressed migration and invasion) in breast cancer cells. Mechanistically, NAT10 regulated TRAF6 expression and stability through ac⁴C modification; NAT10 knockdown led to reduced ac⁴C enrichment on TRAF6 mRNA and accelerated its degradation. Rescue experiments confirmed that TRAF6 overexpression partially reversed the inhibitory effects of NAT10 knockdown on glycolysis and metastasis. In vivo, NAT10 knockdown significantly suppressed tumor growth in nude mice, which was associated with reduced expression of Ki67 and TRAF6 in tumor tissues. Collectively, our findings highlight NAT10 as a key regulator of breast cancer progression via ac⁴C-mediated TRAF6 modulation, suggesting it as a promising therapeutic target for breast cancer therapy.

Keywords:  NAT10; TRAF6; ac⁴C; breast cancer; glycolysis

DOI:  https://doi.org/10.1002/mc.70094
bioRxiv. 2026 Feb 10. pii: 2026.02.08.704727. [Epub ahead of print]

Obesity and Tumor Development Reprogram the Proteome and Metabolic Effects of Adipose- and Tumor-Derived Extracellular Vesicles.

Emma J Grindstaff, Laith A Rayyan, Yazan Alwarawrah, Erika Rezeli, Nancie J MacIver, Dorothy Teegarden, Stephen D Hursting, Ximena Bustamante-Marin.

Obesity alters systemic metabolism and immune function, yet how obesity and tumor progression regulate extracellular vesicle (EV) composition and function within the tumor microenvironment remains unclear. Using a preclinical model of diet-induced obesity (DIO) and triple-negative breast cancer (TNBC), we investigated how obesity and tumor stage shape the proteomic composition of EVs from visceral adipose tissue (VAT-EVs) and mammary tumors (tumor-EVs), and how these EVs regulate immune and tumor cell metabolism. Orthotopically transplanted metM-Wnt lung tumors were classified as early (∼0.5 cm³) or late (∼1.0 cm³), and EV proteomes were analyzed by mass spectrometry. At early stages, tumor-EVs from DIO mice, compared with control lean mice, were depleted in immune-related proteins, whereas VAT-EVs were enriched in mitochondrial and fatty acid oxidation proteins. In contrast, at later stages, tumor-EVs from DIO mice were enriched in lipid metabolism and oxidative stress-associated proteins, while VAT-EVs exhibited loss of mitochondrial proteins consistent with metabolic dysfunction. Functionally, tumor-EVs and VAT-EVs differentially regulated CD8 T cell mitochondrial activity and cytokine production and induced distinct, stage-dependent metabolic reprogramming in non-aggressive epithelial-like (E-Wnt) versus mesenchymal-like (M-Wnt) tumor cells. These findings suggest that obesity and tumor progression dynamically reshapes EV cargo, enabling EV-mediated metabolic reprogramming that may contribute to immune suppression and TNBC progression.

DOI: https://doi.org/10.64898/2026.02.08.704727
Res Sq. 2026 Feb 10. pii: rs.3.rs-8412774. [Epub ahead of print]

Targeting PFKFB3 to enhance CDK4/6 inhibitor response in ER+ breast cancer.

Sucheta Telang, Brian F Clem, Ariamna A Herrera Miret, Leanne Price, Susan M Dougherty, Anna Schmitz, Xinmin Yin, Xipeng Ma, Xiang Zhang, Jason Chesney, Yoannis Imbert-Fernandez.

Background Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are widely used in the treatment of estrogen receptor-positive (ER⁺) breast cancer; however, the metabolic adaptations induced by CDK4/6 inhibition remain incompletely defined. In ER⁺ breast cancer, estrogen signaling plays a central role in coordinating cell cycle progression and metabolic programs that support tumor growth. Glycolytic flux is regulated at the level of phosphofructokinase-1 (PFK1) through the inducible enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), which is transcriptionally regulated by estrogen receptor signaling and has been shown to promote glycolysis and proliferation in ER⁺ breast cancer cells. Yet, how CDK4/6 inhibition intersects with estrogen-regulated glycolytic control to rewire glucose utilization in ER⁺ breast cancer has not been explored. Methods Glucose metabolism was assessed using extracellular flux analysis, untargeted metabolomics, and stable isotope tracing with uniformly labeled 13 C-glucose in ER + breast cancer cell lines. In vivo metabolic tracing was performed following bolus administration of [U- 13 C]-glucose. The effects of pharmacologic PFKFB3 inhibition, alone and in combination with CDK4/6 inhibitors, were evaluated in vitro and in patient-derived xenograft (PDX) models. Statistical analyses were performed using appropriate tests with correction for multiple comparisons where applicable. Results CDK4/6 inhibition increased glycolytic flux, as evidenced by elevated basal and compensatory glycolysis, accumulation of early glycolytic intermediates, and increased 13 C labeling of fructose 1,6-bisphosphate. PFKFB3 silencing abrogated the CDK4/6 inhibitor-induced increase in glycolytic flux. Despite increased glycolysis, stable isotope tracing revealed markedly reduced incorporation of glucose-derived carbon into nucleotide biosynthesis and lipid-associated metabolites, consistent with reduced anabolic demand during G1 cell cycle arrest. In vivo glucose tracing demonstrated a dissociation between increased glycolytic flux and downstream biosynthetic utilization. Pharmacologic inhibition of PFKFB3 imposed additional constrains on glucose utilization and significantly enhanced the antitumor efficacy of CDK4/6 inhibition in PDX models. Conclusions CDK4/6 inhibition rewires glucose metabolism in ER + breast cancer by increasing glycolytic flux while limiting downstream glucose utilization, resulting in heightened reliance on regulated glycolytic control to maintain metabolic homeostasis during cell cycle arrest. Disruption of this adaptive metabolic state through PFKFB3 inhibition enhances the antitumor effects of CDK4/6 inhibition and supports the therapeutic potential of targeting glycolytic regulation in combination with CDK4/6 inhibitor-directed therapies.

DOI: https://doi.org/10.21203/rs.3.rs-8412774/v1
Biochem Biophys Res Commun. 2026 Feb 16. pii: S0006-291X(26)00252-4. [Epub ahead of print]809 153488

Hypoxia-induced LGALS8-AS1 sustains oxidative phosphorylation to drive breast cancer progression.

Huaying Xie, Di Zhou, Zihao Xu, Ye Tian.

  Hypoxia is a defining feature of the breast cancer microenvironment and drives metabolic adaptation during tumor progression. However, the involvement of hypoxia-responsive long noncoding RNAs (lncRNAs) in mitochondrial metabolism remains poorly understood. Here, we identify LGALS8-AS1 as a hypoxia-inducible lncRNA that promotes breast cancer progression by sustaining oxidative phosphorylation (OXPHOS). Transcriptomic profiling of hypoxia-treated T47D and MCF7 cells revealed LGALS8-AS1 as a consistently upregulated lncRNA. LGALS8-AS1 was transcriptionally induced by hypoxia-inducible factor-1α (HIF-1α), as supported by genetic perturbation, promoter reporter assays, and public ChIP-seq data. Genetic deletion of LGALS8-AS1 suppressed tumor growth and metastatic colonization in vivo, whereas re-expression restored these malignant phenotypes. Integrative analysis of the TCGA-BRCA cohort identified oxidative phosphorylation as the pathway most strongly associated with high LGALS8-AS1 expression. Consistently, loss of LGALS8-AS1 impaired mitochondrial respiratory capacity under hypoxia and reduced the expression of key respiratory chain components, particularly Complex I and IV. Pharmacological inhibition of OXPHOS abolished LGALS8-AS1-dependent growth and invasion. These findings establish LGALS8-AS1 as a hypoxia-responsive metabolic regulator that links hypoxia signaling to mitochondrial function in breast cancer.

Keywords:  Breast cancer; Hypoxia; LGALS8-AS1; Mitochondrial respiration; Oxidative phosphorylation

DOI:  https://doi.org/10.1016/j.bbrc.2026.153488
Br J Pharmacol. 2026 Feb 22.

Reprogramming tumour-associated macrophages in breast cancer via si-FOXM1-loaded lipid nanoparticles enhances immune checkpoint inhibitor efficacy.

Yali Gao, Jiayi Li, Mengying Xu, Yaobang Liu, Li Guo, Jinping Li.

   BACKGROUND AND PURPOSE: The polarization state of tumour-associated macrophages (TAMs) plays a crucial role in breast cancer treatment outcomes, particularly in enhancing the efficacy of immune checkpoint inhibitors by transitioning TAMs from the M2 to M1 phenotype. This study aims to investigate whether delivering si-Forkhead Box M1 (FOXM1) efficiently into tumour cells via lipid nanoparticles (LNPs) can silence FOXM1 expression, up-regulate Kruppel-like factor 15 (KLF15) and thereby modulate TAM polarization to enhance the antitumor immune response against breast cancer.
EXPERIMENTAL APPROACH: Transcriptomic data from TCGA and GEO were analysed using Weighted Gene Co-expression Network Analysis (WGCNA) and CIBERSORT for immune infiltration. Cell culture, gene expression, and functional assays assessed the impact of FOXM1 silencing on TAM polarization and breast cancer cell behaviour. si-FOXM1-loaded LNPs were characterized and evaluated both in vitro and in vivo xenograft models.
KEY RESULTS: The study identified KLF15 as a key player associated with breast cancer prognosis and showed that FOXM1 silencing promoted KLF15 expression, leading to reduced M2 macrophage infiltration and inhibited breast cancer progression. LNPs loaded with si-FOXM1 efficiently reprogrammed TAMs to the M1 phenotype, inhibiting breast cancer cell proliferation and invasion.
CONCLUSIONS AND IMPLICATIONS: LNPs loaded with si-FOXM1 act on tumour cells to silence FOXM1 expression and up-regulate KLF15, thereby promoting the reprogramming of tumour-associated macrophages towards the M1 phenotype within the tumour microenvironment. This process effectively inhibits breast cancer progression and enhances the antitumor efficacy of immune checkpoint inhibitors against breast cancer cells.

Keywords:  Forkhead Box M1; Kruppel‐like factor 15; breast cancer; immune checkpoint inhibitor; siRNA lipid nanoparticles; tumour‐associated macrophages

DOI:  https://doi.org/10.1111/bph.70330
Anal Chem. 2026 Feb 23.

Evaluating Therapeutic Efficacy of SCL7A11 and GLUT1 Inhibition in Triple-Negative Breast Cancer via a GSH/ATP Dual-NIR-Responsive Fluorogenic Sensor.

Jiao Lu, Fabiao Yu, Zhirong Geng, Zhilin Wang.

Triple-negative breast cancer (TNBC) lacks receptor expression and exhibits metabolic heterogeneity, leading to ineffective targeted therapy and chemotherapy resistance. There is an urgent need to investigate its metabolic reprogramming mechanisms and develop targeted intervention strategies. In TNBC, the overexpression of a solute carrier family member (SLC7A11) and glucose transporter 1 (GLUT1) drives tumor cell proliferation and survival through excessive glutathione (GSH)/adenosine triphosphate (ATP) production. Whether combined inhibition of SLC7A11 and GLUT1 produces synergistic antitumor effects via oxidative stress and energy imbalance and how GSH/ATP levels change remain unclear. We constructed the first near-infrared dual-activation probe M1219, which successfully visualized the regulatory relationship between oxidative stress and energy imbalance under the stimulation of sulfasalazine (SAS, SLC7A11 inhibitor) and rapamycin A (RgA, GLUT1 inhibitor) by real-time monitoring of the dynamic changes of GSH/ATP in cells. For the first time, we elucidated the NADPH/G6PD/GPX4/ACSL4 axis-mediated metabolic regulatory network under dual-target inhibition. Leveraging the tumor microenvironment's GSH/ATP-specific activation mechanism, M1219 achieved the in vivo visualization of therapeutic efficacy in TNBC mice, validated the enhanced antitumor effect of the combined inhibition strategy, enabled precise resection of TNBC infiltration boundaries (negative margin of <0.1 mm), and successfully distinguished tumor tissue from marginal tissue in clinically resected breast cancer specimens.

DOI: https://doi.org/10.1021/acs.analchem.5c05904
Cell Biochem Funct. 2026 Feb;44(2): e70188

Adipose Tissue Extracellular Matrix Remodeling: A Driver of Obesity and Insulin Resistance.

Imane Nait Irahal, Asmaa Chbel, Ayoub Lafnoune, Bouchra Darkaoui, Hicham Wahnou.

  This review explores the role of extracellular matrix (ECM) in adipose tissue highlighting its composition, regulation, and impact on obesity and insulin resistance. The ECM in adipocytes is a dynamic entity and highly organized network composed of structural proteins which provide mechanical support for cells and tissues and regulate cellular signaling. ECM modifiers, such as matrix metalloproteinases and tissue inhibitors of metalloproteinases, coordinate ECM remodeling to allow the expansion of adipocytes. Furthermore, ECM receptors like integrins and CD44 mediate adipocytes-microenvironment interactions, affecting the inflammatory process resulting in insulin resistance. The ECM components are posttranslational being modified by an array of remodeling enzymes, such as lysyl oxidase and prolyl-4-hydroxylase, to regulate ECM integrity. While excessive ECM deposition and fibrosis urge physical constraints on adipocyte expansion, ECM remodeling emerges as a denominator linking obesity and insulin resistance associated with vascular dysfunction and severe inflammation emphasizing the role of ECM in metabolic diseases.

Keywords:  adipose tissue; extracellular matrix; insulin resistance; obesity; remodeling

DOI:  https://doi.org/10.1002/cbf.70188
J Biochem Mol Toxicol. 2026 Mar;40(3): e70746

Mechanisms of HIF-1α Function in Malignant Cells and Associated Therapeutic Strategies.

Sylvia Yao Sun.

Hypoxia-inducible factor 1-alpha (HIF-1α/HIF1A) is a transcription factor that responds to hypoxia and various other stimuli. HIF-1α plays a pivotal role in cellular adaptation to low oxygen levels by regulating the expression of genes involved in angiogenesis, glycolysis, and erythropoiesis. It activates pathways that enable cell survival under hypoxic conditions, which is essential for processes such as wound healing and tumor progression, and when the proliferation rate of tumors is particularly fast, leading to a decline in oxygen levels. HIF-1α is significantly upregulated in tumor cells and promotes cell invasion, which has been highlighted with the regulatory role of hypoxia in tumor growth by inhibiting apoptosis and tumor cell migration, giving tumor-associated HIF-1α a pro-, and antitumor role in the tumor microenvironment. This context has prompted the development of promising therapeutic strategies targeting cancer, and summarizes clinical trials of HIF-1α-based targeted drugs, immunotherapies, and nanoparticle-based therapies. In summary, this review examined the role and mechanisms of HIF-1α in cancer, emphasizing potential biomarkers and therapeutic targets associated with tumorigenesis.

DOI: https://doi.org/10.1002/jbt.70746
Biomol Biomed. 2026 Feb 27.

Tumor microenvironment and key signaling pathways in breast cancer progression and therapy resistance: A review.

Rui Li, Yujing Wang, Min Xie.

Breast cancer progression is influenced not only by intrinsic tumor alterations but also by reciprocal interactions with the tumor microenvironment (TME), a complex ecosystem comprising fibroblasts, immune and endothelial cells, adipocytes, extracellular matrix components, soluble mediators, and extracellular vesicles. This review synthesizes recent basic and translational research on how TME-derived signals activate dysregulated signaling pathways, including the phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin (PI3K/AKT/mTOR), transforming growth factor beta/SMAD (TGF-β/SMAD), Janus kinase/signal transducer and activator of transcription (JAK/STAT), mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), Wingless-related integration site/beta-catenin (Wnt/β-catenin), Notch, Yes-associated protein/transcriptional co-activator with PDZ-binding motif (YAP/TAZ), and nuclear factor kappa B (NF-κB). These pathways promote key processes such as invasion, angiogenesis, adaptation to hypoxia, epithelial-mesenchymal transition, immune evasion, cancer stemness, and therapy resistance. We emphasize convergent findings that indicate the feedback loop between tumor cells and the TME sustains plasticity and drug-tolerant states. Additionally, we summarize emerging therapeutic strategies, including stromal and extracellular matrix normalization, immunotherapy combinations, pathway-targeted inhibitors, and nanotechnology-enabled drug delivery. A comprehensive understanding of TME-signaling crosstalk is crucial for overcoming therapeutic resistance in breast cancer.

DOI: https://doi.org/10.17305/bb.2026.13708
Pharm Res. 2026 Feb 25.

Silencing CD24 Inhibits Proliferation, Migration, and Chemoresistance in Triple-Negative Breast Cancer Cells.

Yanli Liu, Yuhan Guo, Chien-Yu Lin, Yuanyuan Zhang, Guangfu Li, Kun Cheng.

   PURPOSE: The expression of CD24 is significantly higher in triple-negative breast cancer (TNBC) compared to estrogen receptor and progesterone receptor-positive (ER+ PR+) breast cancer and normal breast tissue. CD24 overexpression is associated with tumorigenesis, metastasis, and drug resistance in TNBC. Moreover, CD24 functions as a "don't eat me" signal and disrupts macrophages-mediated phagocytosis of cancer cells. We, therefore, aim to investigate the therapeutic potential of downregulating CD24 in TNBC cells.
METHODS: We designed four CD24 siRNAs and evaluated their silencing efficiency and biological activity in TNBC cells using different methods. We also examined the impact of CD24 silencing on doxorubicin resistance and macrophage-mediated phagocytosis of TNBC cells.
RESULTS: We have identified a CD24 siRNA that exhibits potent silencing activity in TNBC cells, effectively inhibiting their proliferation, migration, and invasion. CD24 silencing also induces apoptosis of TNBC cells and arrests the cell cycle in the S phase. Moreover, silencing CD24 enhances the sensitivity of TNBC cells to doxorubicin and increases macrophage-mediated phagocytosis of TNBC cells.
CONCLUSIONS: Targeting CD24 with siRNAs is a promising therapeutic strategy for TNBC and other cancers characterized by CD24 overexpression.

Keywords:  CD24; SiRNA; TNBC; chemoresistance; macrophage; phagocytosis

DOI:  https://doi.org/10.1007/s11095-026-04046-y
Mol Pharm. 2026 Feb 22.

Hypoxia-Responsive Retinoid Liposomes for Tumor Microenvironment-Activated Differentiation and Metastasis Suppression.

Chunlin Li, Di Liu, Xiaojie Li, Deqi Zhu, Hong Zhang, Yonglian Wang.

  Cancer stem-like cells (CSCs) are a key driving factor of tumor heterogeneity, metastasis, and chemoresistance. All-trans retinoic acid (ATRA) shows strong potential for inducing CSC differentiation and reducing stemness; however, its clinical translation is limited by the lack of effective targeting and favorable biodistribution under physiological conditions. Here, we report a hypoxia-responsive ATRA-phospholipid conjugate (RAPC) as a delivery and differentiation-priming strategy, enabling the fabrication of ATRA-loaded liposomes (ATRA@Lip) with high drug loading and microenvironment-activated release. RAPC was synthesized via a modular route incorporating an azobenzene-based hypoxia-cleavable linker between ATRA and a phosphatidylcholine analog. By coassembling RAPC with cholesterol and phospholipid, stable liposomes were obtained with a maximal ATRA loading of 17 wt % at 50 mol % RAPC content. Under normoxia, ATRA@Lip exhibited minimal leakage, whereas hypoxic conditions triggered rapid azo bond cleavage and accelerated ATRA release. Functionally, hypoxia-triggered ATRA@Lip promoted CSC differentiation and enhanced the chemosensitivity of breast cancer cells to albumin-bound paclitaxel (Nab-PTX) in vitro. Collectively, this hypoxia-responsive lipid-drug conjugate platform enables functional CSC priming and improved combination chemotherapy, offering a promising strategy for microenvironment-activated modulation of CSC-associated chemoresistance in metastatic breast cancer.

Keywords:  cancer therapy; controlled release; drug delivery; drug resistance; phospholipid–drug conjugates

DOI:  https://doi.org/10.1021/acs.molpharmaceut.5c01284
Cell Death Dis. 2026 Feb 24.

CRMP2 inhibits metastasis formation by impairing ILF3-dependent stabilization of CXCL10 mRNA in breast cancer.

Binyan Lin, Mei Luo, Yanqing Zhou, Xin Liu, Qin Zhu, Zebin Weng, Lei Li, Tao Cao, Jing Sun, Dawei Yang, E-Hu Liu.

Tumor-derived elements contribute to the formation of the pre-metastatic niche (PMN) and facilitate cancer metastasis, but much less is known about the key molecular mechanisms. Here, we demonstrate that collapsin response mediator protein 2 (CRMP2), a critical regulator of the cytoskeleton, is associated with metastasis in breast cancer. CRMP2 overexpression inhibits both lung metastasis and PMN formation in breast cancer. Mechanistically, CRMP2 overexpression leads to downregulation of CXCL10. We also found that the correlation between CRMP2 and CXCL10 is mediated by interleukin enhancer-binding factor 3 (ILF3). The D-hydantoinases (D-HYD) fragment of CRMP2 specifically interacts with the second double-stranded RNA binding motif (dsRBM2) of ILF3. Overexpressed CRMP2 reduces the expression of ILF3 in proteasome-dependent degradation via Lys 48-linked polyubiquitination at Lys257, Lys332 and Lys413. In addition, ILF3 directly binds to CXCL10 mRNA, thereby increasing CXCL10 mRNA stability. Finally, we found that psoralen interacts with CRMP2 and suppresses the development of lung metastases in breast cancer. In conclusion, our findings uncover a critical CRMP2-related mechanism behind breast tumor metastasis, and the CRMP2-ILF3-CXCL10 axis may provide a potential therapeutic strategy for controlling breast cancer metastasis.

DOI: https://doi.org/10.1038/s41419-026-08515-5
Cancer Lett. 2026 Feb 24. pii: S0304-3835(26)00112-6. [Epub ahead of print] 218349

Targeting PCK1 to overcome CDK4/6 inhibitor resistance for breast cancer therapy.

Chen-Shiou Wu, Hsiao-Fan Chen, Kieu-Thanh Huynh, Wei-Chien Huang, Yi-Chuan Li, Wei-Chao Chang, Ling-Chu Chang, Ciao-Ling Jiang, Kevin Chih-Yang Huang, Liang-Chih Liu, K S Clifford Chao, Mien-Chie Hung.

  Phosphoenolpyruvate carboxykinase 1 (PCK1) is known for its role in gluconeogenesis and the regulation of PCK1 expression was shown to associate with oncogenic activity in pancreatic and colorectal cancers. However, in different cancer types such as liver cancer, PCK1 could function as a tumor suppressor, rendering complication for targeted therapy. In this study, we used breast cancer model to delineate its involvement in malignancy, we found PCK1 associated with oncogenic function to promotes cell proliferation, enhances colony formation, and stimulates DNA synthesis in breast cancer. Mechanistically, we found that PCK1 interacts with Cyclin D3, establishing a positive correlation between PCK1 and Cyclin D3 in clinical breast cancer tissues. Cyclin D3 forms a complex with CDK4/6, implicated in the development of resistance to CDK4/6 inhibitors. We identified PCK1 as a key factor in this resistance. Through an extensive screening process, we identified everolimus and auranofin as inhibitors of PCK1. We found that these drugs, in combination with CDK4/6 inhibitors, exhibit a synergistic effect in suppressing breast cancer. These findings reveal the connection between PCK1 and CDK4/6 inhibitor resistance, offering the possibility for improved treatment options for breast cancer. Interestingly, we also found PCK1 and Cyclin D3 interaction in pancreatic cancer, similar to that in breast cancer, but not in liver cancer. Thus, the results may resolve the puzzle for the role of PCK1 in tumor-promoting or -suppressive role in different cancer types.

Keywords:  CDK4/6 inhibitor; Cyclin D3; PCK1; breast cancer; drug resistance

DOI:  https://doi.org/10.1016/j.canlet.2026.218349