The HDAC inhibitor SB939 overcomes resistance to BCR-ABL kinase Inhibitors conferred by the <i>BIM</i> deletion polymorphism in chronic myeloid leukemia

<div><p>Chronic myeloid leukemia (CML) treatment has been improved by tyrosine kinase inhibitors (TKIs) such as imatinib mesylate (IM) but various factors can cause TKI resistance in patients with CML. One factor which contributes to TKI resistance is a germline intronic deletion polymorphism in the <i>BCL2-like 11</i> (<i>BIM</i>) gene which impairs the expression of pro-apoptotic splice isoforms of <i>BIM</i>. SB939 (pracinostat) is a hydroxamic acid based HDAC inhibitor with favorable pharmacokinetic, physicochemical and pharmaceutical properties, and we investigated if this drug could overcome <i>BIM</i> deletion polymorphism-induced TKI resistance. We found that SB939 corrects <i>BIM</i> pre-mRNA splicing in CML cells with the <i>BIM</i> deletion polymorphism, and induces apoptotic cell death in CML cell lines and primary cells with the <i>BIM</i> deletion polymorphism. More importantly, SB939 both decreases the viability of CML cell lines and primary CML progenitors with the <i>BIM</i> deletion and restores TKI-sensitivity. Our results demonstrate that SB939 overcomes <i>BIM</i> deletion polymorphism-induced TKI resistance, and suggest that SB939 may be useful in treating CML patients with <i>BIM</i> deletion-associated TKI resistance.</p></div

SB939, in combination with IM, significantly reduces the colony-forming ability of CML cell lines with the <i>BIM</i> deletion polymorphism.

<p>Results of apoptotic cell death, as assessed by flow cytometry-based Annexin V assay, for K562 (A) <i>BIM</i>^<i>i2+/+</i>, (C) <i>BIM</i>^<i>i2+/-</i> and (E) <i>BIM</i>^<i>i2-/-</i> cells are shown. The P values were based on Student’s <i>t</i> test. Apoptotic cell death: *P = 0.0078 and ^#P = 5 X 10⁻⁴ in (A), *P = 0.011 and ^#P = 9.6 X 10⁻⁴ in (C), *P = 0.018 and ^#P = 0.0033 in (E), were calculated by comparing with their respective DMSO-treated control samples. **P = 0.0022 and ^##P = 0.0013 in (A), **P = 0.0032 and ^##P = 4.8 X 10⁻⁴ in (C), **P = 3.3 X 10⁻⁴ and ^##P = 10⁻⁴ in (E), were calculated in comparison with samples treated with IM only. Results of the colony formation assay for K562 (B) <i>BIM</i>^<i>i2+/+</i>, (D) <i>BIM</i>^<i>i2+/-</i> and (F) <i>BIM</i>^<i>i2-/-</i> cells are shown. Colony formation for each sample was calculated as a percentage of the total number of colonies counted from the corresponding DMSO-treated control. The P values were based on Student’s <i>t</i> test. Colony formation assay: ⁺P = 0.0045, ^P = 0.0047, *P = 6 X 10⁻⁵ and ^#P = 3 X 10⁻⁵ in (B), *P = 0.0059 and ^#P = 0.0014 in (D), were calculated by comparing their respective colony formation to that of the DMSO controls. ⁺⁺P = 0.0038, ^^P = 4.8 X 10⁻⁴, **P = 0.0026 and ^##P = 0.0035 in (B), ^P = 0.041, **P = 0.014 and ^##P = 0.015 in (D), *P = 0.038 and ^#P = 0.029 in (F), were calculated by comparing their respective colony formation to that of the sample treated with IM only. Cells were treated with either or both SB939 (0-1000nM) and imatinib (2uM) for 72 hours. All results are given as the mean ± s.e.m (n = 3).</p

SB939 reduces the viability of primary CML progenitors with the <i>BIM</i> deletion polymorphism.

<p>Results of apoptotic cell death, as assessed by flow cytometry-based Annexin V assay, for primary CML cells (A) without (n = 3) and (C) with (n = 2) the <i>BIM</i> deletion polymorphism are shown. Results of the colony formation assay for primary CML cells (B) without (n = 3) and (D) with (n = 4) the <i>BIM</i> deletion polymorphism are shown. Colony formation for each sample was calculated as a percentage of the total number of colonies counted from the corresponding DMSO-treated control. The P values were based on Student’s <i>t</i> test. ⁺P = 0.033, *P = 10⁻⁴ and ^#P = 2.8 X 10⁻⁴ in (B), *P = 0.0075 and ^#P = 10⁻⁶ in (D) were calculated by comparing their respective colony formation to that of the DMSO controls. ⁺⁺P = 0.0023, ^P = 0.0025, **P = 0.0071 and ^##P = 0.0025 in (B), ⁺P = 0.038, ^P = 0.021, **P = 0.019 and ^##P = 0.017 in (D) were calculated by comparing their respective colony formation to that of the sample treated with IM only. Cells were treated with either or both SB939 (0-1000nM) and imatinib (2uM) for 72 hours. All results are given as the mean ± s.e.m.</p

Spatial transcriptomics reveal topological immune landscapes of Asian head and neck angiosarcoma

Abstract Angiosarcomas are rare malignant tumors of the endothelium, arising commonly from the head and neck region (AS-HN) and recently associated with ultraviolet (UV) exposure and human herpesvirus-7 infection. We examined 81 cases of angiosarcomas, including 47 cases of AS-HN, integrating information from whole genome sequencing, gene expression profiling and spatial transcriptomics (10X Visium). In the AS-HN cohort, we observed recurrent somatic mutations in CSMD3 (18%), LRP1B (18%), MUC16 (18%), POT1 (16%) and TP53 (16%). UV-positive AS-HN harbored significantly higher tumor mutation burden than UV-negative cases (p = 0.0294). NanoString profiling identified three clusters with distinct tumor inflammation signature scores (p < 0.001). Spatial transcriptomics revealed topological profiles of the tumor microenvironment, identifying dominant but tumor-excluded inflammatory signals in immune-hot cases and immune foci even in otherwise immune-cold cases. In conclusion, spatial transcriptomics reveal the tumor immune landscape of angiosarcoma, and in combination with multi-omic information, may improve implementation of treatment strategies

Cholangiocarcinoma: Recent Advances in Molecular Pathobiology and Therapeutic Approaches

Cholangiocarcinomas (CCA) pose a complex challenge in oncology due to diverse etiologies, necessitating tailored therapeutic approaches. This review discusses the risk factors, molecular pathology, and current therapeutic options for CCA and explores the emerging strategies encompassing targeted therapies, immunotherapy, novel compounds from natural sources, and modulation of gut microbiota. CCA are driven by an intricate landscape of genetic mutations, epigenetic dysregulation, and post-transcriptional modification, which differs based on geography (e.g., for liver fluke versus non-liver fluke-driven CCA) and exposure to environmental carcinogens (e.g., exposure to aristolochic acid). Liquid biopsy, including circulating cell-free DNA, is a potential diagnostic tool for CCA, which warrants further investigations. Currently, surgical resection is the primary curative treatment for CCA despite the technical challenges. Adjuvant chemotherapy, including cisplatin and gemcitabine, is standard for advanced, unresectable, or recurrent CCA. Second-line therapy options, such as FOLFOX (oxaliplatin and 5-FU), and the significance of radiation therapy in adjuvant, neoadjuvant, and palliative settings are also discussed. This review underscores the need for personalized therapies and demonstrates the shift towards precision medicine in CCA treatment. The development of targeted therapies, including FDA-approved drugs inhibiting FGFR2 gene fusions and IDH1 mutations, is of major research focus. Investigations into immune checkpoint inhibitors have also revealed potential clinical benefits, although improvements in survival remain elusive, especially across patient demographics. Novel compounds from natural sources exhibit anti-CCA activity, while microbiota dysbiosis emerges as a potential contributor to CCA progression, necessitating further exploration of their direct impact and mechanisms through in-depth research and clinical studies. In the future, extensive translational research efforts are imperative to bridge existing gaps and optimize therapeutic strategies to improve therapeutic outcomes for this complex malignancy

Claudin-1 Has Tumor Suppressive Activity and Is a Direct Target of RUNX3 in Gastric Epithelial Cells

Gastroenterology1381GAST