bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2026–05–10
nineteen papers selected by
Kelsey Fisher-Wellman, Wake Forest University
  1. Targeting NDUFS4 Disrupts Oxidative Phosphorylation and Induces Ferroptosis in Olaparib-Resistant Prostate Cancer.
  2. HER2-driven mammary tumorigenesis enhances bioenergetics despite reductions in mitochondrial content.
  3. Metformin inhibits mitochondrial complex I in intestinal epithelium to promote glycaemic control.
  4. Succinate dehydrogenase loss suppresses pyrimidine biosynthesis via succinate-mediated inhibition of aspartate transcarbamylase.
  5. Aconitase 2 the rescue: A safeguard against excess mitochondrial citrate.
  6. AcTor, a novel mTOR stimulator, potentiates ixazomib for the treatment of acute myeloid leukemia.
  7. Metformin lowers blood glucose by targeting intestinal mitochondrial complex I.
  8. Leukemic stem cell subtypes determine venetoclax resistance and therapeutic vulnerabilities in AML.
  9. Succinate calls a time-out on pyrimidine biosynthesis.
  10. CPT1B promotes acute myeloid leukemia progression via fatty acid oxidation-dependent metabolic reprogramming.
  11. Age distinguishes selection from causation in cancer genomes.
  12. Transposable elements shape stemness in normal and leukemic hematopoiesis.
  13. Mitochondrial ETF insufficiency drives neoplastic growth by selectively optimizing cancer bioenergetics.
  14. The BTN3A3-TOMM22 axis preserves mitochondrial homeostasis to facilitate HCC stemness and drug resistance.
  15. Complex I protein NDUFB9 is a metabolic vulnerability in triple negative breast cancer brain metastases.
  16. CRISPR base editor screening identifies spectrum of MEN1 mutations impacting menin inhibitors in clinical trials.
  17. 'Undruggable' cancer proteins meet their match.
  18. VGF-Mediated Mitochondrial Remodeling Fuels Lung Adenocarcinoma Brain Metastasis.
  19. Combining Menin and MEK inhibition to target poor prognosis KMT2A-rearranged RAS pathway-mutant acute myeloid leukemia.
  1. Mol Cancer Ther. 2026 May 05. OF1-OF13
    Targeting NDUFS4 Disrupts Oxidative Phosphorylation and Induces Ferroptosis in Olaparib-Resistant Prostate Cancer.
    Zachary A Schaaf, Shu Ning, Amy R Leslie, Masuda Sharifi, Richard Y Gao, James P Maine, Kristina D Leslie, Yuqiu Shen, Alan P Lombard, Wei Lou, Pui-Kai Li, Chengfei Liu, Marc Dall'Era, Allen C Gao.
      Resistance to poly(ADP-ribose) polymerase inhibitors (PARPi) remains a major challenge in the treatment of advanced prostate cancer. Although metabolic rewiring has been implicated in this process, the molecular drivers and therapeutic vulnerabilities underlying this adaptation remain poorly defined. We integrated transcriptomic, functional, and clinical analyses to identify mitochondrial regulators of PARPi resistance. RNA sequencing and gene set enrichment analysis revealed robust enrichment of oxidative phosphorylation (OxPhos) pathways in PARPi-resistant prostate cancer cells, with consistent upregulation of NDUFS4, a nuclear-encoded subunit of electron transport chain complex I. Elevated NDUFS4 expression correlated with poor survival in patient cohorts from The Cancer Genome Atlas and SU2C/PCF. Functional analyses demonstrated that genetic knockdown of NDUFS4 impaired complex I activity, reduced mitochondrial mass, and resensitized resistant cells to olaparib. Pharmacologic targeting of NDUFS4 using the niclosamide analog ARVib-7 phenocopied genetic depletion, suppressing mitochondrial respiration and enhancing olaparib efficacy to inhibit the growth of resistant spheroids. Both NDUFS4 silencing and ARVib-7 treatment induced ferroptotic stress, as evidenced by intracellular iron accumulation and altered expression of ferroptosis-associated markers, including COX2, CHAC1, NRF2, and GPX4. These findings identify NDUFS4 as a key mediator of PARPi resistance and a therapeutic vulnerability in advanced prostate cancer. Targeting NDUFS4 disrupts OxPhos and induces ferroptosis, providing a strong rationale for combination strategies with PARPis to overcome drug resistance.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-25-1157
  2. Elife. 2026 May 06. pii: RP104079. [Epub ahead of print]14
    HER2-driven mammary tumorigenesis enhances bioenergetics despite reductions in mitochondrial content.
    Sara M Frangos, Henver S Brunetta, Dongdong Wang, Maria Joy Therese Jabile, Leslie M Jeffries, Grace Mencfeld, David W L Ma, William J Muller, Cezar M Khursigara, Kelsey H Fisher-Wellman, Jim Petrik, Gregory R Steinberg, Graham P Holloway.
      It is now recognized that mitochondria play a crucial role in tumorigenesis; however, it has become clear that tumor metabolism varies significantly between cancer types. The failure of recent clinical trials aimed at directly targeting tumor respiration through oxidative phosphorylation inhibitors underscores the critical need for further studies providing an in-depth evaluation of mitochondrial bioenergetics. Accordingly, we comprehensively assessed the bulk tumor and mitochondrial metabolic phenotype in murine HER2-driven mammary cancer tumors and benign mammary tissue. Transcriptomic and proteomic profiling revealed a broad downregulation of mitochondrial genes/proteins in tumors, including OXPHOS subunits comprising Complexes I-IV. Despite reductions in tumor mitochondrial proteins, mitochondrial respiration was several-fold higher compared to benign mammary tissue, which persisted regardless of normalization method (wet weight, total protein content, and when corrected for mitochondrial content). This upregulated respiratory capacity could not be explained by OXPHOS uncoupling, suggesting HER2 signaling regulates intrinsic mitochondrial bioenergetics. In further support, lapatinib, an EGFR/HER2 tyrosine kinase inhibitor, attenuated mitochondrial respiration in NF639 murine mammary tumor epithelial cells. Together, this data highlights that the typical correlation between mitochondrial content and respiratory capacity may not apply to all tumor types and implicates HER2-linked activation of mitochondrial respiration supporting tumorigenesis in this model.
    Keywords:  HER2; bioenergetics; cancer biology; cancer metabolism; cell biology; mitochondria; mouse; proteomics; transcriptomics
    DOI:  https://doi.org/10.7554/eLife.104079
  3. Nat Metab. 2026 May 08.
    Metformin inhibits mitochondrial complex I in intestinal epithelium to promote glycaemic control.
    Zachary L Sebo, Ram P Chakrabarty, Rogan A Grant, Karis B D'Alessandro, Alec R Koss, Jenna L E Blum, Shawn M Davidson, Colleen R Reczek, Navdeep S Chandel.
      Metformin is a versatile biguanide drug primarily prescribed for type II diabetes. Despite its extensive use, the mechanisms underlying its clinical effects, including attenuated postprandial glucose excursions and elevated intestinal glucose uptake, remain unclear. Here we map these and other effects of metformin to intestine-specific mitochondrial complex I inhibition. Using human metabolomic data and an orthogonal genetics approach in male mice, we demonstrate that metformin suppresses citrulline synthesis, a metabolite generated exclusively by small intestine mitochondria, and increases GDF15 by inhibiting the mitochondrial respiratory chain at complex I. This inhibition co-opts the intestines to function as a glucose sink, driving the uptake of excess glucose and its conversion to lactate and lactoyl-phenylalanine. We also find that glucose lowering by metformin is due to repeated bolus exposure rather than a cumulative chronic response. Notably, the efficacy of phenformin, another biguanide, and berberine, a structurally unrelated nutraceutical, similarly depends on intestine-specific mitochondrial complex I inhibition, underscoring a shared therapeutic mechanism.
    DOI:  https://doi.org/10.1038/s42255-026-01530-y
  4. Nat Metab. 2026 May 04.
    Succinate dehydrogenase loss suppresses pyrimidine biosynthesis via succinate-mediated inhibition of aspartate transcarbamylase.
    Madeleine L Hart, David Sokolov, Serwah Danquah, Eric Zheng, Alex D Doan, Kristian Davidsen, David MacPherson, Lucas B Sullivan.
      Decreased availability of the amino acid aspartate constrains cell function across diverse biological contexts, but the temporal interplay between aspartate abundance, downstream metabolic changes and functional effects remains poorly understood. Here we show that succinate dehydrogenase (SDH) inhibition suppresses pyrimidine synthesis via dual effects of cellular aspartate depletion and succinate accumulation. Using an aspartate biosensor and live-cell imaging, we monitor aspartate levels and cell proliferation across several models of aspartate limitation. While complex I inhibition or knockout of aspartate biosynthetic enzymes lead to a strict decrease in aspartate levels and impair proliferation, SDH inhibition produces a unique aspartate rebound, yet fails to restore proliferation. Mechanistically, we find that SDH loss impairs pyrimidine biosynthesis via succinate accumulation, which competitively inhibits aspartate utilization by mammalian aspartate transcarbamylase (ATCase), a key step in pyrimidine biosynthesis. This metabolic interaction occurs in multiple models of SDH deficiency, causing pyrimidine insufficiency, replication stress and sensitivity to ATR kinase inhibition. Taken together, these findings define an unexpected role for succinate in modulating cellular nucleotide homeostasis and demonstrate how cascading metabolic interactions can unfold to impact cell function.
    DOI:  https://doi.org/10.1038/s42255-026-01524-w
  5. Mol Cell. 2026 May 07. pii: S1097-2765(26)00244-3. [Epub ahead of print]86(9): 1595-1597
    Aconitase 2 the rescue: A safeguard against excess mitochondrial citrate.
    Edrees H Rashan, Sophie D'Halleweyn, Matthew G Vander Heiden.
      In a recent issue of Cell, Xie et al.1 report that an important function of mitochondrial aconitase is to limit toxic citrate accumulation, suggesting a role for the canonical TCA cycle in physiology beyond ATP production and precursor biosynthesis.
    DOI:  https://doi.org/10.1016/j.molcel.2026.04.010
  6. Res Sq. 2026 Apr 23. pii: rs.3.rs-9405584. [Epub ahead of print]
    AcTor, a novel mTOR stimulator, potentiates ixazomib for the treatment of acute myeloid leukemia.
    Shakti P Pattanayak, Odai Darawshi, Omid Hajihassani, Jordan M Winter, Nicole Weiler, Melanie Ott, Florian Rothweiler, Jindrich Cinatl, Martin Michaelis, Daniel J Lindner, Thomas D Green, Polina Krassovskaia, Raphael T Aruleba, Kelsey H Fisher-Wellman, Jason A Mears, David Wald, Leif A Eriksson, Boaz Tirosh.
      Background mTORC1 activity is oncogenic. However, in the presence of chemotherapy, suppression of mTORC1 is cytoprotective. mTOR suppression requires an intact tuberous sclerosis complex (TSC), composed of TSC1, TSC2 and TBC1D7. Small molecules that activate mTOR by blocking the TSC are lacking. Methods We applied in silico docking and medicinal chemistry to generate AcTor, a potential first-of-its-kind TSC2 inhibitor. Because inhibition of TSC2 results in increased sensitivity to proteasome inhibitors, we combined AcTor and the proteasome inhibitor ixazomib (IXZ) in various cancer cell types. Results Potentiation of cytotoxic activity of IXZ by AcTor was observed across multiple acute myeloid leukemia (AML) cell lines and primary patient samples. The combination triggered a collapse of mitochondrial respiratory capacity, loss of mitochondrial membrane potential, accumulation of ROS and apoptosis. These attributes increased in drug-resistant AML. Transcriptomic profiling revealed that AcTor alone induced anabolic and oxidative phosphorylation programs, whereas AcTor/IXZ redirected the signaling towards stress-associated and pro-apoptotic transcriptional states, including a p53 pathway signature. In vivo studies revealed reduction in AML burden, depletion of blasts and of leukemic stem cells, and retention of activity upon relapse. AcTor/IXZ was equally potent in a TP53 -mutated patient-derived xenograft model, exceeding the efficacy of standard-of-care. Conclusions As a TSC2 inhibitor, AcTor should not be used alone in cancer. When combined with proteasome inhibitors, the pharmacodynamics of AcTor shifts towards the development of a mitochondrial catastrophe in AML, which is durable, broad range, agnostic to TP53 mutations and to the acquisition of resistance to common clinical anti-AML drugs.
    DOI:  https://doi.org/10.21203/rs.3.rs-9405584/v1
  7. Nat Metab. 2026 May 08.
    Metformin lowers blood glucose by targeting intestinal mitochondrial complex I.
      
    DOI:  https://doi.org/10.1038/s42255-026-01532-w
  8. Cell Stem Cell. 2026 May 07. pii: S1934-5909(26)00152-9. [Epub ahead of print]
    Leukemic stem cell subtypes determine venetoclax resistance and therapeutic vulnerabilities in AML.
    Alexander Waclawiczek, Aino-Maija Leppä, Simon Renders, Ines Bergerweiss, Karolin Stumpf, Barbara Betz, Susanna Gabrowski, Frank Y Huang, Maria-Eleni Lalioti, Bendix Hempel, Markus Sohn, Heikki Kuusanmäki, Vera Thiel, Julia M Unglaub, Rabia Shahswar, Sarah Richter, Maike Janssen, Darja Karpova, Elisa Donato, Halvard Bonig, Christoph Röllig, Simon Raffel, Michael Heuser, Michael Hundemer, Mika Kontro, Ann-Kathrin Eisfeld, Tim Sauer, Nina Cabezas-Wallscheid, Carsten Müller-Tidow, Andreas Trumpp.
      The BCL-2 inhibitor venetoclax has transformed the treatment of acute myeloid leukemia (AML), but relapse due to resistance of leukemic stem cells (LSCs) remains a major challenge. By molecular and functional profiling of LSCs from >150 patients, we identify four LSC subtypes. These mirror distinct hematopoietic lineage stages, which determine the expression ratio between the venetoclax target BCL-2 and resistance-inducing proteins MCL-1 and BCL-xL (MAC-score). Longitudinal analyses reveal that venetoclax resistance mostly arises in LSCs through plasticity toward a megakaryocytic/erythroid-progenitor (MEP)-LSC state that switches survival dependency from BCL-2 to BCL-xL. In rare cases, mature monocytic/dendritic (MoDe)-LSCs, found within LAMP5+ monocytic AMLs, drive venetoclax resistance. LSC subtyping improves genetic risk stratification and provides subtype-specific therapies: venetoclax-resistant MEP-LSCs respond to BCL-xL inhibitors, whereas MoDe-LSCs are sensitive to MEK1/2 inhibition. Our findings reveal four distinct LSC types with unique vulnerabilities and propose biomarker-guided treatment strategies that complement genetic profiling to overcome venetoclax resistance.
    Keywords:  BCL-2; MAC-score; acute myeloid leukemia; azacitidine; chemotherapy; leukemic stem cells; personalized medicine; plasticity; therapy resistance; venetoclax
    DOI:  https://doi.org/10.1016/j.stem.2026.04.012
  9. Nat Metab. 2026 May 04.
    Succinate calls a time-out on pyrimidine biosynthesis.
    Désirée Schatton, Christian Frezza.
      
    DOI:  https://doi.org/10.1038/s42255-026-01523-x
  10. Transl Oncol. 2026 May 07. pii: S1936-5233(26)00140-3. [Epub ahead of print]69 102803
    CPT1B promotes acute myeloid leukemia progression via fatty acid oxidation-dependent metabolic reprogramming.
    Rui Cao, Ling-Ling Zhou, Qi Liu, Guo-E Liu, Ling Xu, Han He.
       BACKGROUND: Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with limited treatment options, especially in cases of relapse or refractory disease. Metabolic reprogramming, particularly fatty acid oxidation (FAO), has emerged as a critical mechanism in AML progression. Carnitine palmitoyltransferase 1B (CPT1B), a rate-limiting enzyme in mitochondrial FAO, is highly expressed in metabolically active tissues, yet its role in AML remains poorly defined.
    METHODS: CPT1B expression was analyzed using TCGA datasets, patient samples, and AML cell lines. Functional studies employed CPT1B knockdown (shRNA) and overexpression (lentiviral) models in AML cell lines (THP-1, KG-1, HL-60, HEL). In vitro and in vivo effects were assessed via CCK-8, flow cytometry, western blot, ELISA, and xenograft models in immunodeficient mice. The FAO inhibitor Etomoxir was used to evaluate metabolic dependency.
    RESULTS: CPT1B was significantly overexpressed in AML tissues and cell lines compared to normal controls and correlated with poorer overall survival. CPT1B knockdown reduced proliferation, induced G0/G1 cell cycle arrest, and promoted apoptosis in AML cells. CPT1B silencing inhibited tumor growth and dissemination in vivo. Conversely, CPT1B overexpression enhanced FAO activity, increased lipid droplet accumulation, and upregulated PPARA, CPT1A, and ACOX1 expression. Treatment with Etomoxir reversed these effects, restoring apoptosis and inhibiting CPT1B-driven proliferation both in vitro and in mouse models.
    CONCLUSIONS: CPT1B acts as a key metabolic driver of AML progression through FAO-dependent lipid metabolic reprogramming. Its inhibition suppresses leukemic growth and improves survival outcomes, identifying the CPT1B-FAO axis as a promising therapeutic target and prognostic biomarker in AML.
    Keywords:  Acute myeloid leukemia; Apoptosis; CPT1B; Etomoxir; Fatty acid oxidation; Metabolic reprogramming
    DOI:  https://doi.org/10.1016/j.tranon.2026.102803
  11. Nat Genet. 2026 May 05.
    Age distinguishes selection from causation in cancer genomes.
    David Cheek, Martin Blohmer, Martin A Nowak, Tibor Antal, Kamila Naxerova.
      Cancer-causing mutations have been identified primarily from positive selection signals in cancer genomes. However, positive selection is also a ubiquitous feature of normal tissue aging. Here we develop a statistical framework to disentangle selection in normal tissue and causation of carcinogenesis. By comparing cancer and normal tissue genomes, we estimate the effects of mutations on cancer risk in the blood, esophagus and colon. We determine that stronger cancer-causing mutations are enriched at younger patient ages. This enables cancer-causing mutations to be identified from patient age distributions, even without normal tissue data. Moreover, we show for acute myeloid leukemia that the age-dependence of purported causal mutations can be explained largely by normal blood evolution, challenging the long-standing notion that childhood cancers require distinct mutations. Broadly, our framework delineates carcinogenesis from normal tissue aging, improving the assessment of cancer risk conferred by mutations.
    DOI:  https://doi.org/10.1038/s41588-026-02593-z
  12. Nat Genet. 2026 May 04.
    Transposable elements shape stemness in normal and leukemic hematopoiesis.
    Giacomo Grillo, Bettina Nadorp, Aditi Qamra, Bryce Drylie, Amanda Mitchell, Christopher Arlidge, Ankita Nand, Naoya Takayama, Alex Murison, Seyed Ali Madani Tonekaboni, Komaldeep Kaur Kang, Andrea Arruda, Jean C Y Wang, Mark D Minden, Özgen Deniz, Héléna Boutzen, John E Dick, Mathieu Lupien.
      Despite most acute myeloid leukemia (AML) patients achieving complete remission after induction chemotherapy, two-thirds relapse within 5 years. AML follows a cellular hierarchy sustained by leukemia stem cells (LSCs), which drive tumor progression and relapse. Little is known about the genetic determinants driving LSCs stemness properties. By identifying chromatin variants from accessibility measurements across LSCs, hematopoietic stem cells and downstream progeny, we identified transposable elements (TEs) as genetic determinants of primitive versus mature populations. Accessibility at 121 TE subfamilies distinguished LSCs from mature leukemic cells and stratified AML patients by stemness and survival. Functional assays revealed that these TE subfamilies serve as docking sites for genome topology regulators or lineage-specific transcription factors, including LYL1 in LSCs. Chromatin editing established the necessity of accessibility at LTR12C elements to maintain LSC stemness. Thus, TEs regulate primitive versus mature cell states, with distinct subfamilies underlying stemness in normal versus leukemic stem cells.
    DOI:  https://doi.org/10.1038/s41588-026-02585-z
  13. Elife. 2026 May 05. pii: RP106587. [Epub ahead of print]14
    Mitochondrial ETF insufficiency drives neoplastic growth by selectively optimizing cancer bioenergetics.
    David Papadopoli, Ranveer Palia, Predrag Jovanovic, Sébastien Tabariès, Emma Ciccolini, Valerie Sabourin, Sebastian Igelmann, Shannon McLaughlan, Lesley Zhan, HaEun Kim, Nabila Chekkal, Krzysztof J Szkop, Thierry Bertomeu, Jibin Zeng, Julia Vassalakis, Farzaneh Afzali, Slim Mzoughi, Ernesto Guccione, Mike Tyers, Daina Avizonis, Ola Larsson, Lynne-Marie Postovit, Sergej Djuranovic, Josie Ursini-Siegel, Peter M Siegel, Michael Pollak, Ivan Topisirovic.
      Mitochondrial electron transport flavoprotein (ETF) insufficiency causes metabolic diseases known as a multiple acyl-CoA dehydrogenase deficiency (MADD). In contrast to muscle, ETFDH is a non-essential gene in acute lymphoblastic leukemia NALM6 cells, and its expression is reduced across human cancers. In various human cancer cell lines and mouse models, ETF insufficiency caused by decreased ETFDH expression limits flexibility of OXPHOS fuel utilisation but paradoxically increases bioenergetics and accelerates neoplastic growth via activation of the mTORC1/BCL-6/4E-BP1 axis. Collectively, these findings reveal that while ETF insufficiency is rare and has detrimental effects in non-malignant tissues, it is common in neoplasia, where ETFDH downregulation leads to bioenergetic and signaling reprogramming that accelerates neoplastic growth.
    Keywords:  cancer biology; cell biology; human; mRNA translation; metabolism; mouse; signal transduction
    DOI:  https://doi.org/10.7554/eLife.106587
  14. Cancer Lett. 2026 Apr 30. pii: S0304-3835(26)00320-4. [Epub ahead of print] 218557
    The BTN3A3-TOMM22 axis preserves mitochondrial homeostasis to facilitate HCC stemness and drug resistance.
    Xiaofeng Kang, Guanglin Lei, Xiaobo Hou, Yimeng Du, Minghao Xu, Chunyuan Xue, Donghui Liu, Songhao Jia, Jingbo Shan, Chuanhao Tang, Xiaojie Xu, An Xu.
      Cancer stemness drives malignant progression and drug resistance in hepatocellular carcinoma (HCC). Although mitochondrial dynamics are known to influence HCC development, the precise mechanisms linking mitochondrial function to stemness remain largely elusive. Integrating bulk and single-cell transcriptomics, we identified Butyrophilin Subfamily 3 Member A3 (BTN3A3) as a novel oncogene driving HCC stemness. BTN3A3 depletion markedly reduced sphere formation, stemness-related gene expression, and the percentage of CD90+/EpCAM+ cancer stem cells. Rescue experiments confirmed that BTN3A3 promotes HCC cell proliferation, migration, and invasion. Furthermore, BTN3A3 depletion sensitized HCC cells to sorafenib by inducing ROS accumulation and apoptosis. Mechanistically, mass spectrometry and Co-IP identified TOMM22 as a key mitochondrial interactor of BTN3A3. Crucially, sorafenib stress actively promotes BTN3A3 mitochondrial translocation, where it shields TOMM22 from ubiquitin-proteasome-dependent degradation. BTN3A3 deficiency led to TOMM22 depletion, mitochondrial fragmentation, and impaired oxidative phosphorylation (OXPHOS) and ATP production. Importantly, silencing TOMM22 reversed BTN3A3-mediated stemness and sorafenib resistance. In vivo orthotopic xenograft models and patient-derived organoids (PDOs) further validated that BTN3A3 correlates with stemness and malignant tumor growth. Utilizing 5E08, a pan-BTN3 monoclonal antibody, markedly suppressed tumor growth and concurrently downregulated TOMM22 expression in vivo. In conclusion, our study unveils a previously unrecognized non-immunological role for BTN3A3 in mitochondrial reprogramming. We demonstrate that BTN3A3 drives HCC stemness and drug resistance by preventing TOMM22 ubiquitination to maintain mitochondrial homeostasis. These findings position BTN3A3 as a promising therapeutic target, with the pan-BTN3 monoclonal antibody 5E08 offering a potential strategy to overcome stemness-driven malignancy and resistance in HCC patients.
    Keywords:  BTN3A3; Cancer stemness; Hepatocellular carcinoma; Sorafenib resistance; TOMM22
    DOI:  https://doi.org/10.1016/j.canlet.2026.218557
  15. Nat Commun. 2026 May 09.
    Complex I protein NDUFB9 is a metabolic vulnerability in triple negative breast cancer brain metastases.
    Mingxi Lin, Zhexu Wen, Cheng Zeng, Yizi Jin, Teng Zhou, Yuxin Yan, Shenglin Huang, Xin Hu, Xiaoxiang Guan, Xichun Hu, Jian Zhang.
      Triple-negative breast cancer (TNBC) brain metastases (BrMs) remain a therapeutic challenge. We depict the discrepancies between primary tumors and BrMs, and examine patient-matched cerebrospinal fluid and plasma to provide detailed profiles of BrMs' metabolic microenvironment. High-throughput in vivo loss of function CRISPR screens identify NDUFB9 (NADH: Ubiquinone Oxidoreductase Subunit B9) as a brain-specific metabolic vulnerability. NDUFB9-knockout selectively inhibits the BrMs outgrowth without affecting extracranial metastases. Mechanistically, TNBC cells exhibit an imbalance between aspartate upstream supply and downstream biosynthetic demand. NDUFB9-knockout disrupts mitochondrial complex I and reduces intracellular aspartate, but this alone is insufficient to inhibit TNBC proliferation. Instead, the lower asparagine concentration in the brain microenvironment induces compensatory upregulation of asparagine synthetase, which further diverts aspartate toward asparagine biosynthesis. This dual-hit mechanism exhausts the aspartate pool and restricts nucleotide biosynthesis, thereby selectively suppressing BrM outgrowth. Our findings uncover a therapeutic strategy for TNBC BrMs.
    DOI:  https://doi.org/10.1038/s41467-026-72927-2
  16. Nat Commun. 2026 May 09.
    CRISPR base editor screening identifies spectrum of MEN1 mutations impacting menin inhibitors in clinical trials.
    Wallace Bourgeois, Hannah E Rice, Daniela V Wenge, Florian Perner, Hong Yue, Brandon D Regalado, George Wan, Jan C Schroeder, Alba Sommerschield, Charlie Hatton, Shivendra Singh, Sweta Singh, Shipra Bijpuria, Brian M McKeever, William H Miller, Jordan F Safer, Sumaiya Iqbal, Jennifer A Perry, Eric S Fischer, John G Doench, Gerard M McGeehan, Jevon A Cutler, Scott A Armstrong.
      Menin inhibitors have entered clinical trials for histone lysine methyltransferase 2 A (KMT2A)-rearranged and nucleophosmin 1 (NPM1)-mutant acute leukemias and are demonstrating promising activity. CRISPR base editor screening previously predicted several MEN1 (menin) mutations that have arisen in patients receiving SNDX-5613 and confer resistance. The extent to which MEN1 mutations will impact each menin inhibitor is mostly unknown. Here we show that CRISPR base editor screens can be leveraged to profile the MEN1 mutations that may impact five different menin inhibitors in clinical trials. We identify shared (M327I/V/T, G331D) and inhibitor-specific (C334R, E368K/V, V372A) resistance mutations. Co-crystal structures of menin bound to each menin inhibitor suggest resistance mechanisms related to how each inhibitor engages the KMT2A binding pocket of menin. Orthogonal in vitro and in vivo MEN1 mutation generation under therapeutic pressure suggest the MEN1 mutations identified with CRISPR base editor screening are likely to arise and impact all menin inhibitors.
    DOI:  https://doi.org/10.1038/s41467-026-72685-1
  17. Nature. 2026 May 08.
    'Undruggable' cancer proteins meet their match.
      
    Keywords:  Cancer
    DOI:  https://doi.org/10.1038/d41586-026-01447-2
  18. Cancer Res. 2026 May 04. 86(9): 2104-2125
    VGF-Mediated Mitochondrial Remodeling Fuels Lung Adenocarcinoma Brain Metastasis.
    Yibei Wang, Xinyue Sheng, Yi Yang, Chen Liu, Shubao Wang, Ruixi Guo, Yue Gu, Ming Chen, Hongyan Zhang, Jingjing Du, Xiaoxue Qin, Ziwei Miao, Pengfei Wu, Xiujuan Qu, Bo Li.
      Lung adenocarcinoma cells exhibit a marked propensity for brain metastasis, in which they face unique metabolic challenges imposed by the microenvironment. The mechanisms that enable lung adenocarcinoma cells to adapt to these constraints represent potential therapeutic targets. In this study, we identified the neuropeptide VGF as a clinically relevant driver of brain metastatic progression. VGF expression was markedly upregulated in lung adenocarcinoma brain metastases, and elevated VGF expression was associated with an increased risk of brain metastasis and poor survival outcomes. Moreover, brain-derived signals induced VGF expression in lung adenocarcinoma cells, promoting cell survival and proliferation through enhanced mitochondrial oxidative phosphorylation and ATP production. Mechanistically, the N-terminal domain of VGF-a nonclassically secreted peptide-interacted with the hydrolase domain of ABHD12B to suppress cardiolipin degradation, leading to increased cardiolipin levels, stabilization of mitochondrial membranes, and a shift toward mitochondrial fusion over excessive fission. These changes helped meet the heightened energetic demands of metastatic cells in the brain. Genetic deletion of the VGF N-terminal domain disrupted mitochondrial fusion, impaired oxidative metabolism, and significantly reduced brain colonization in mouse models of brain metastasis. Together, these findings uncover a role for VGF and establish the VGF-ABHD12B-cardiolipin axis as a critical mechanism underlying metabolic adaptation in lung adenocarcinoma brain metastases, highlighting the potential of this pathway as a therapeutic target for intervention.
    SIGNIFICANCE: The N-terminal domain of VGF is required for sustaining mitochondrial fusion and oxidative phosphorylation to support metabolic adaptation in lung cancer brain metastases, underscoring a potentially targetable mechanism to impair brain colonization.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-2712
  19. Blood Adv. 2026 May 05. pii: bloodadvances.2025016208. [Epub ahead of print]
    Combining Menin and MEK inhibition to target poor prognosis KMT2A-rearranged RAS pathway-mutant acute myeloid leukemia.
    Nastassja Keora Scheidegger, Constanze Schneider, Gabriela Alexe, Yi-Cheng Wang, Todd A Alonzo, Allen Basanthakumar, Wallace A Bourgeois, Julia Dudkiewicz-Garbicz, Delan Khalid, Lucy A Merickel, Jennifer A Perry, Rhonda E Ries, Silvi Salhotra, Audrey Taillon, Alan S Gamis, Richard Aplenc, Marian H Harris, Mark Wunderlich, Scott A Armstrong, Jessica A Pollard, Soheil Meshinchi, Yana Pikman, Kimberly Stegmaier.
      KMT2A-rearranged (KMT2A-r) acute leukemias are especially prevalent in the pediatric population. KMT2A-fusion proteins drive leukemogenic gene expression through an interaction with a chromatin complex that includes the scaffold protein menin, giving rise to aggressive acute leukemias. RAS pathway mutations are also common in pediatric leukemia. In a cohort of 1750 patients enrolled on Children's Oncology Group (COG) trials, we identified RAS pathway mutations in 43% of AML cases. The presence of RAS pathway mutations in KMT2A-r AML was associated with a lower complete remission (CR) rate, poor event-free (EFS) and overall survival (OS), and early relapses. Given the inferior outcome observed for children with dual mutations, we next sought to identify efficacious targeted drug combinations for this subset of childhood leukemia. We evaluated RAS/MAPK targeting using the MEK1/2 inhibitor selumetinib in combination with the menin inhibitor revumenib. Treatment of AML cell lines and cultured leukemia cells from patient-derived xenograft (PDX) models resulted in a synergistic decrease in viability and promoted cell cycle arrest, apoptosis and downregulation of Myc targets in the combination compared to each drug alone. In vivo, the combination treatment of AML pediatric PDX models harboring KMT2A-r and RAS mutations reduced leukemia burden compared to single drug treatments, but without improving overall survival compared to menin inhibition alone. Our preclinical study suggests a potential targeted treatment combination for KMT2A-r and RAS pathway mutant leukemia, but one which will require further optimization. COG completed clinical trials AAML03P1, AAML0531, AAML1031 and C2961.
    DOI:  https://doi.org/10.1182/bloodadvances.2025016208
This page is being maintained by Thomas Krichel. It was last updated on 2026‒05‒10 at 1:20.