KDM6A (Lysine Demethylase 6A)

Our analysis revealed unique clinicopathological characteristics and genetic markers in FD-associated sarcomas, deepening our knowledge of the mechanisms behind malignant transformation in FD and offering diagnostic tools for enhanced pathological assessment.

Notably, 25(OH)D exhibited a synergistic effect with GSK-J4, a specific inhibitor of KDM6A, in suppressing breast cancer cell growth. Collectively, our findings uncover a novel anticancer mechanism of 25(OH)D, highlight the critical role of KDM6A Δexon13 in breast cancer progression, and provide further evidence supporting the correction of 25(OH)D deficiency in breast cancer patients.

In summary, KDM6A deficiency predominates in urothelial neoplasms but also occurs in many further tumor entities. Whether KDM6A deficient cancers are susceptible to EZH2 inhibitors remains to be seen.

Pharmacological inhibition of USP7 with FT671 and XL177A reduces KDM6A stability and viral receptor expression, and confers resistance to MERS-CoV, SARS-CoV, and all major SARS-CoV-2 variants of concern, including those resistant to remdesivir in primary human airway and intestinal epithelial cells. In mice, FT671 treatment was well tolerated, reduced Ceacam1 expression, and protected against MHV-A59 infection. Collectively, our findings unveil an antagonistic ubiquitin-mediated regulatory circuit that controls KDM6A stability, viral receptor levels, and coronavirus infection.

Furthermore, we discuss emerging therapeutic strategies for KMT2C-deficient breast cancers, such as epigenetic modulators (EZH2 inhibitors, KDM6A inhibitors, and BET inhibitors), DNA damage response (DDR)-targeting agents, and pathway-specific inhibitors. These insights not only elucidate the complex biological functions of KMT2C in breast cancer but also provide a rationale for developing precision therapies tailored to KMT2C-mutant tumours.

In AML, it correlated with CD33 expression and inv(16)/t(16;16). In conclusion, mesothelin is rare in ALL but enriched in specific AML subtypes and not prognostic for survival.

These findings indicate that Kdm6a promotes fibrosis in TSC through the activation of the MAPK/ERK/SNAI1 signaling pathway. Moreover, the combination of mTORC1 and KDM6A inhibitors results in marked regression of fibrosis and liver lesions in TSC models, unveiling a potential treatment for TSC patients with inadequate response to mTORC1 inhibitors.

Here, we identify that loss-of-function mutations in KDM6A, a histone demethylase altered in about 26% of advanced bladder cancers, are associated with poor survival after cisplatin chemotherapy, whereas they correlate with improved outcomes with anti-PD-1 therapy...This metabolic shift diminishes histone lactylation in regulatory T cells, suppressing immunoregulatory genes and limiting expansion of PD-1hi regulatory T cells. Collectively, our findings establish KDM6A mutation as a key regulator of therapeutic responses, providing a foundation for its use in guiding precision therapy in advanced bladder cancer.

Cytogenetic analysis revealed triple molecular aberrations including a t(1;6) (p31;q25) translocation, a TET2 frameshift deletion (44.1% VAF), and a KDM6A missense mutation (c.262G>A, 46.6% VAF). The patient died within 6 months post-diagnosis, suggesting that this aggressive clinical course may be associated with a novel clinicogenetic subtype of BPDCN.

Furthermore, KDM6A inhibition in combination with cisplatin, resulted in an increased tumor regression in vivo. Our study thus highlights the importance of KDM6A as a therapeutic target in preventing CRC growth and relapse which can have future therapeutic implications.

These findings highlight the need to molecularly characterize these lesions as there is no specific histologic finding to identify cases that harbour different pathogenic alterations in specific genes.

Alterations in FGFR3, commonly found in the luminal-papillary molecular subtype associated with low response to immunotherapy, are the target of erdafitinib. Enfortumab vedotin, which targets Nectin-4 (expressed in >95% of urothelial carcinomas), is approved for patients who progress after chemotherapy and/or immunotherapy...Sacituzumab govitecan, an antibody-drug conjugate directed against Trop-2, is effective in basal, luminal and stroma-rich subtypes but not in neuroendocrine carcinomas. In addition, therapies developed for HER2-positive breast cancer have shown efficacy in urothelial carcinoma, with recent data from the DESTINY pan-tumour phase II trial leading to FDA approval of trastuzumab deruxtecan for HER2-overexpressing metastatic urothelial carcinoma. This paper is a comprehensive review of the molecular pathology of bladder cancer, highlighting advances in molecular classification, biomarkers and personalized therapies. The transition from morphology-based classifications to combined morphological and molecular approaches, with therapeutic implications, is also addressed.