ArticleClinical cancer research : an official journal of the American Association for Cancer Research2023
Suppression of Tumor Cell Lactate-generating Signaling Pathways Eradicates Murine PTEN/p53-deficient Aggressive-variant Prostate Cancer via Macrophage Phagocytosis.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers, 1 of them a synthesis that pooled it.
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Who cites it
59 citing papers in PubMed, 1 synthesis or guideline pooled it, 49 citations in OpenAlex.
- Mapping research trends in macrophage polarization and immunotherapeutic potential in prostate cancer: a bibliometric and visual analysis.Frontiers in oncology · 2026Pooled it
- Tumor‑immune spatiotemporal co‑evolution: A new paradigm for understanding and overcoming therapy resistance in metastatic castration‑resistant prostate cancer (Review).International journal of molecular medicine · 2026Review
- Article
- Protein lactylation in health and diseases: molecular mechanisms, biological significance, and clinical implications.Signal transduction and targeted therapy · 2026Review
- Lactylation-driven therapeutic resistance in cancer: Mechanisms and therapeutic opportunities.Genes & diseases · 2026Review
- Novel therapeutic strategies for metastatic castration‑resistant prostate cancer: Beyond androgen receptor pathway inhibition (Review).International journal of oncology · 2026Review
- Targeting Lactate and Lactylation in Cancer Metabolism and Immunotherapy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- Lactate metabolism and lactylation in cancer: from pathogenesis to therapeutic advances.Signal transduction and targeted therapy · 2026Review
- Histone Lactylation in Immune Cells and Its Predictive Role in Sepsis Progression: A Prospective Observational Study.Shock (Augusta, Ga.) · 2026Observational
- Novel Insights into the Role of circRNAs in Cancer Immunotherapy Resistance and Clinical Implications.International journal of molecular sciences · 2026Review
- Lactate metabolism-driven lactylation: paradoxical modulation of intestinal inflammation and malignancy.Journal of translational medicine · 2026Review
- Targeting phase separation: a new strategy to disrupt the stromal-immune axis in colorectal cancer.Cell communication and signaling : CCS · 2026Review
- Lactylation formation, gene regulation, biological functions, and clinical relevance.Histology and histopathology · 2026Review
- Review
- Lactylation in cancer: molecular mechanisms and advances in clinical study.Molecular cancer · 2026Review
- Bulk and single cell RNA sequencing data reveal lactylation-related gene signatures for prognosis and immunity in cervical cancer.Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas · 2026Article
- CD24 and Mutant p53: Emerging Therapeutic Targets in Prostate Cancer Progression.Anti-cancer agents in medicinal chemistry · 2026Review
- Integrated Proteogenomic Characterization Identifies Breast Cancer Immune Subgroups and Subtype-Specific Therapeutic Strategies.Research (Washington, D.C.) · 2026Article
- Metabolic symbiosis and competition: the dual nature of TAM-tumor cell cross-talk in tumor progression.Frontiers in oncology · 2026Review
- From mechanism to targeted therapy: Advances in histone lactylation-driven cancer progression (Review).Oncology letters · 2026Review
Corrections and comments
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Authors and funding
13 authors at 3 institutions in 1 country.
Funding
Abstract
purposePhosphatase and tensin homolog (PTEN) loss-of-function/PI3K pathway hyperactivation is associated with poor therapeutic outcomes and immune checkpoint inhibitor resistance across multiple malignancies. Our prior studies in Pb-Cre;PTENfl/flTrp53fl/fl genetically engineered mice (GEM) with aggressive-variant prostate cancer (AVPC) demonstrated tumor growth control in 60% mice following androgen deprivation therapy/PI3K inhibitor (PI3Ki)/programmed cell death protein 1 (PD-1) antibody combination, via abrogating lactate cross-talk between cancer cells and tumor-associated macrophages (TAM), and suppression of histone lactylation (H3K18lac)/phagocytic activation within TAM. Here, we targeted immunometabolic mechanism(s) of PI3Ki resistance, with the goal of durable tumor control in AVPC. EXPERIMENTAL
designPb-Cre;PTENfl/flTrp53fl/fl GEM were treated with PI3Ki (copanlisib), MEK inhibitor (trametinib) or Porcupine inhibitor (LGK'974) singly or their combinations. MRI was used to monitor tumor kinetics and immune/proteomic profiling/ex vivo coculture mechanistic studies were performed on GEM tumors or corresponding tumor-derived cell lines.
resultsGiven our proteomic profiling showing persistent MEK signaling within tumors of PI3Ki-resistant GEM, we tested whether addition of trametinib to copanlisib enhances tumor control in GEM, and we observed 80% overall response rate via additive suppression of lactate within TME and H3K18lac within TAM, relative to copanlisib (37.5%) monotherapy. The 20% resistant mice demonstrated feedback Wnt/β-catenin activation, resulting in restoration of lactate secretion by tumor cells and H3K18lac within TAM. Cotargeting Wnt/β-catenin signaling with LGK'974 in combination with PI3Ki/MEKi, demonstrated durable tumor control in 100% mice via H3K18lac suppression and complete TAM activation.
conclusionsAbrogation of lactate-mediated cross-talk between cancer cells and TAM results in durable ADT-independent tumor control in PTEN/p53-deficient AVPC, and warrants further investigation in clinical trials.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.