bims-necame Biomed News
on Metabolism in small cell neuroendocrine cancers
Issue of 2026–03–15
seven papers selected by
Grigor Varuzhanyan, UCLA
  1. Entinostat Induces Dual Apoptotic and Autophagic Cell Death in Small-Cell Lung Cancer via Epigenetic Modulation of HDAC1-p53-AMPK/mTOR Axis.
  2. Effect of ABHD4 on biological behavior of small cell lung cancer and its mechanism of action.
  3. Clinically actionable molecular alterations in Rb-retained small cell lung carcinoma variants.
  4. Subtype-specific dependencies and therapeutic opportunities in small cell lung cancer.
  5. 177Lu-labelled peptide receptor radionuclide therapy in patients with neuroendocrine tumors: a systematic review and meta-analysis.
  6. Molecular Characterization of KLK2 RNA Expression in Prostate Cancer.
  7. Molecular taxonomy of pancreatic neuroendocrine tumors reveals BEND2-fusions-driven transcriptional plasticity and therapeutic vulnerabilities.
  1. J Biochem Mol Toxicol. 2026 Mar;40(3): e70720
    Entinostat Induces Dual Apoptotic and Autophagic Cell Death in Small-Cell Lung Cancer via Epigenetic Modulation of HDAC1-p53-AMPK/mTOR Axis.
    Zhongkai Tong, Xiaoxiao Zhu, Cenli Wang, Mengqing Hu, Xiaofei Liang, Chunli Wu, Zhenyan Li, Lin He, Zhaoxing Dong, Yong Zhou.
      Entinostat, a selective HDAC1/3 inhibitor, has shown anti-tumor activity in small cell lung cancer (SCLC), but the precise molecular mechanisms underlying its efficacy remain incompletely understood. This study aimed to investigate the functional role and mechanism of Entinostat in SCLC, with a focus on HDAC1 inhibition and its downstream effects on cell death pathways. The anti-tumor effects of Entinostat were evaluated in SCLC cell lines and a xenograft mouse model using MTT, flow cytometry, immunofluorescence, western blotting, and rescue experiments with HDAC1 overexpression and pathway-specific inhibitors. We found that Entinostat significantly inhibited SCLC cell viability and induced both apoptosis and autophagy. Mechanistically, Entinostat downregulated HDAC1 protein levels, increased p53 acetylation and phosphorylation, activated AMPK, and suppressed mTOR signaling. HDAC1 overexpression reversed these molecular changes and attenuated Entinostat-induced cytotoxicity. In vivo, Entinostat suppressed tumor growth and consistently modulated the HDAC1/p53/AMPK/mTOR pathway. In conclusion, Entinostat exerts potent anti-tumor activity in SCLC by simultaneously inducing apoptosis and autophagy through epigenetic modulation of p53 via HDAC1 inhibition and subsequent regulation of the AMPK/mTOR axis.
    Keywords:  Entinostat; acetylation; apoptosis; autophagic; p53; small cell lung cancer
    DOI:  https://doi.org/10.1002/jbt.70720
  2. J Thorac Dis. 2026 Feb 28. 18(2): 120
    Effect of ABHD4 on biological behavior of small cell lung cancer and its mechanism of action.
    Jingjing Chen, Zaixin Yuan, Xi Yin, Mengjiao Wang, Yan Zhang, Jian Feng, Liqin Xu.
       Background: Small cell lung cancer (SCLC) is a highly aggressive malignancy with limited therapeutic options. ABHD4, a member of the lipid-metabolizing enzyme family, has been implicated in various cancers, but its precise role and molecular mechanisms in SCLC remain poorly understood. The aim of this study was to investigate the functional impact of ABHD4 on SCLC progression and to explore its potential links with lipid metabolism and the PI3K/AKT/mTOR signaling pathway.
    Methods: The study analyzed ABHD4 expression in clinical SCLC specimens and cell lines. Functional characterization was performed using ABHD4 knockdown in xenograft models and cancer cells to assess effects on tumor growth, proliferation, migration, invasion, and apoptosis. Metabolomic profiling was employed to examine lipid metabolism changes. Mechanistic studies focused on the PI3K/AKT/mTOR pathway, and curcumin treatment was used to interrogate ABHD4-associated phenotypes in H69 cells.
    Results: ABHD4 was consistently upregulated in SCLC samples compared to normal controls. Its knockdown significantly impaired tumor growth in vivo and reduced cancer cell proliferation, migration, and invasion while promoting apoptosis. Metabolomic analysis confirmed a connection between ABHD4 expression and altered lipid metabolism. Mechanistically, ABHD4 was identified as a key factor associated with the PI3K/AKT/mTOR pathway. Furthermore, curcumin treatment effectively attenuated the oncogenic phenotypes linked to ABHD4 overexpression.
    Conclusions: This study demonstrates that ABHD4 contributes to SCLC progression, associates with modulations in lipid metabolism, and is linked to the PI3K/AKT/mTOR signaling pathway. The findings suggest ABHD4 as a potential therapeutic target, with curcumin showing promise in mitigating its oncogenic effects.
    Keywords:  ABHD4; PI3K/AKT/mTOR; curcumin; lipid metabolism; small cell lung cancer (SCLC)
    DOI:  https://doi.org/10.21037/jtd-2025-1854
  3. Virchows Arch. 2026 Mar 11.
    Clinically actionable molecular alterations in Rb-retained small cell lung carcinoma variants.
    Martin Zacharias, Nikolaus John, Karl Kashofer, Helmut Popper.
      Small cell lung carcinoma (SCLC) is classically defined by biallelic inactivation of RB1 and TP53. However, a small subset of tumors retains Rb expression and exhibits distinct molecular features. Here, we report two Rb-retained SCLC cases that expand the biological and therapeutic spectrum of this subgroup. Both tumors occurred in middle-aged women, showed small cell morphology with some variant features, and displayed complex copy number alterations. Case 1 harbored a truncal KRAS p.G12C mutation with high-level amplification of chromosome 11q13-q14, including CCND1, and demonstrated a clinical response to sotorasib. Case 2 harbored a TP53 mutation, CDKN2A loss, STK11 inactivation, and a novel IKZF2::ERBB4 fusion. These findings highlight the molecular heterogeneity of Rb-retained SCLC and demonstrate that this subgroup can harbor clinically actionable oncogenic drivers. Accordingly, routine assessment of Rb expression in SCLC, followed by comprehensive molecular profiling of Rb-retained tumors, is warranted to uncover therapeutically relevant targets.
    Keywords:  Molecular profiling; Pulmonary neuroendocrine neoplasms; RB1; Small cell lung carcinoma; Targeted therapy
    DOI:  https://doi.org/10.1007/s00428-026-04458-6
  4. Sci Adv. 2026 Mar 13. 12(11): eaea6225
    Subtype-specific dependencies and therapeutic opportunities in small cell lung cancer.
    Amanda Luvisotto, Rima Tulaiha, Lu Wang.
      Small cell lung cancer (SCLC), accounting for ~15% of lung cancers, is an aggressive and lethal tumor type. It is characterized by rapid proliferation, early metastasis, and poor prognosis. Current therapies, including platinum-based chemotherapy and recently introduced immune checkpoint inhibitors, provide modest survival benefits due to frequent relapse and therapeutic resistance. At the molecular level, SCLC is marked by near-universal loss of the tumor suppressors genes TP53 and RB1, and exhibits marked heterogeneity driven by several key master transcription factors. These factors define distinct molecular subtypes with unique gene expression programs and therapeutic vulnerabilities, enabling cell plasticity and subtype switching in response to treatment pressures. A thorough understanding of these subtype-specific dependencies and the epigenetic mechanisms regulating transcription is critical for developing effective and durable therapies. This review focuses on these aspects and evaluates the potential of epigenetic-targeted strategies in the treatment of SCLC.
    DOI:  https://doi.org/10.1126/sciadv.aea6225
  5. Front Endocrinol (Lausanne). 2026 ;17 1758639
    177Lu-labelled peptide receptor radionuclide therapy in patients with neuroendocrine tumors: a systematic review and meta-analysis.
    Jingrong Wang, Xangyi Pang, Jie Lian, Haibo Lu.
       Objective: This systematic review and meta-analysis evaluated the efficacy and safety of 177Lu-labelled peptide receptor radionuclide therapy (PRRT) in neuroendocrine tumors (NETs).
    Methods: This systematic review and meta-analysis conducted a search of the PubMed/MEDLINE, Embase, and Web of Science databases. Included studies assessed treatment outcomes using Response Evaluation Criteria in Solid Tumors (RECIST) or World Health Organization (WHO) criteria. A random-effects model was used to calculate pooled proportions.
    Results: A total of 14 studies with 1844 patients were included. The pooled disease control rate (DCR) was 87.6% (95% Confidence Interval (CI), 82.5%-92%), and the objective response rate (ORR) was 32.2% (95% CI, 25.4%-39.3%). Median progression-free survival (PFS) was 30.87 months (95% CI, 22.71-39.04), and median overall survival (OS) was 51.85 months (95% CI, 39.99-63.71). Subgroup analysis revealed a significantly higher DCR in grade 1-2 NETs 97.7% (95% CI, 91.4%-100%) compared to grade 3 NETs 90.8% (95% CI, 85.1%-94.4%), and a higher ORR in grade 1-2 tumors 45.4% (95% CI, 35.3%-55.6%) compared to grade 3 tumors 27.1% (95% CI, 21.2%-33.4%). PFS was longer in pancreatic NETs 93.9 months (95% CI, 39.45-148.35) than in gastrointestinal NETs 66.32 months (95% CI, 41.78-90.87). The overall incidence of adverse events was 4.1%, with grade ≥3 toxicities in 4.3%. 177Lu-PRRT demonstrates high efficacy and a favorable safety profile in treating NETs.
    Conclusion: 177Lu-DOTA-Tyr3-octreotate (177Lu-DOTATATE) demonstrates high efficacy and a favorable safety profile in treating NETs.
    Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD420251047030.
    Keywords:  177Lu-DOTATATE; gastroenteropancreatic NETs; meta-analysis; neuroendocrine tumor; peptide receptor radionuclide therapy
    DOI:  https://doi.org/10.3389/fendo.2026.1758639
  6. Clin Cancer Res. 2026 Mar 12.
    Molecular Characterization of KLK2 RNA Expression in Prostate Cancer.
    Rana R McKay, Shayan S Nazari, Andrew Elliott, Norm Smith, Pedro Barata, Deepak Kilari, Rohan Garje, Michael C Haffner, Colm Morrissey, Brent A Rupnow, Subhasree Basu, Charles Drake, Brent Rose, Aditya Bagrodia, Neeraj Agarwal, Emmanuel S Antonarakis, Himisha Beltran.
       PURPOSE: KLK2 is an androgen-regulated gene critical in prostate cancer biology with multiple KLK2-targeted therapies in clinical development. We investigated KLK2 RNA expression patterns and associations with molecular features to provide context for emerging KLK2-targeted treatments.
    EXPERIMENTAL DESIGN: DNA/RNA next-generation sequencing was performed on 7,078 prostate cancer specimens. KLK2-high/low RNA expression was defined as ≥75th/<25th percentiles (transcripts per million, TPM). KLK2 expression was evaluated across histologic subtypes, disease states, and metastatic sites, with correlative analyses of genomic alterations, RNA signatures, and clinical outcomes.
    RESULTS: KLK2 gene expression varied significantly by histology, with highest levels in adenocarcinoma (8.79 log2[TPM+1]) and minimal expression in histologic neuroendocrine prostate cancer (0.33 log2[TPM+1]). Expression was significantly higher in androgen deprivation therapy (ADT)/androgen receptor pathway inhibitor (ARPI)-sensitive versus ADT/ARPI-exposed tumors (8.97 vs. 8.38 log2[TPM+1], q<0.001). Localized tumors demonstrated higher expression than lymph node (8.93 vs. 8.76 log2[TPM+1]) or distant metastases (8.23 log2[TPM+1]), with visceral metastases showing the lowest levels. In the overall cohort, KLK2 expression correlated positively with androgen receptor signaling (r=0.25-0.47) and negatively with neuroendocrine signaling. High KLK2 expression was associated with significantly improved overall survival (93.9 vs. 74.4 months, hazard ratio 0.68, p<0.001) in the total cohort, with similar patterns in patients with ADT/ARPI-sensitive and ADT/ARPI-exposed disease.
    CONCLUSIONS: This large-scale clinico-genomic analysis reveals distinct KLK2 expression patterns across prostate cancer histologies, tumor sites, and clinical states. These findings provide a molecular framework understanding KLK2 as a therapeutic target in prostate cancer.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-25-4293
  7. Cell Rep Med. 2026 Mar 06. pii: S2666-3791(26)00059-5. [Epub ahead of print] 102642
    Molecular taxonomy of pancreatic neuroendocrine tumors reveals BEND2-fusions-driven transcriptional plasticity and therapeutic vulnerabilities.
    Xiaofan Lu, Philippe Baltzinger, Li Xu, Antonin Fattori, Sehrish Khan Bazai, Fatima Alhourani, Marie-Pierrette Chenard, Philippe Bachellier, Pietro Addeo, Véronique Debien, Clara Vacheret, Alessio Imperiale, Patrick Pessaux, Wenxuan Cheng, Martin Balzinger, Jean-Emmanuel Kurtz, Irwin Davidson, Xiaoping Su, Bernard Goichot, Gabriel G Malouf.
      Pancreatic neuroendocrine tumors (pNETs) exhibit substantial clinical and molecular heterogeneity. Using bulk and single-nucleus RNA sequencing, we identify five molecular subtypes: Hedgehog-high, Alpha-like, Hypoxia-high, Gastrin-high, and Progenitor-like. The Gastrin-high and Progenitor-like subtypes associate with poor clinical outcomes. BEND2 gene fusions occur in 5% of pNETs, all belonging to the Gastrin-high subtype, which shows activation of the late endocrine progenitor FEV regulon. Functional studies in pNET cell models demonstrate that BEND2 fusions drive transcriptional reprogramming, promoting a shift from ASCL1+ endocrine states toward neurodevelopmental, mesenchymal, and immune-related gene programs. Single-nucleus analysis reveals complex multicellular ecosystems, with NOTCH3-mediated signaling between tumor cells and myofibroblasts emerging as a potential therapeutic vulnerability. Gastrin-high tumors exhibit CD8+ T cell infiltration alongside PD-1/PD-L1 upregulation, suggesting potential responsiveness to immune checkpoint blockade. These findings define a molecular taxonomy of pNETs and nominate tumor-intrinsic and microenvironmental programs as actionable targets.
    Keywords:  BEND2 fusions; clinical outcome; pancreatic neuroendocrine tumors; progenitor cells; transcriptional reprogramming
    DOI:  https://doi.org/10.1016/j.xcrm.2026.102642
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