Objective Patients with glioblastoma (GB) have a median survival of 15 months, despite intensive treatment with surgical resection, radiotherapy, and chemotherapy. A major challenge in overcoming treatment resistance is intratumoral heterogeneity, characterized by molecular, phenotypic, and clinical diversity. Small-molecule inhibitors (SMIs) target specific oncogenic signaling pathways and have become successful therapies in several molecularly defined cancers. In GB, however, SMIs have thus far failed to substantially improve patient outcomes. Here, we used a primary patient-derived glioblastoma organoid (PGO) platform to investigate adaptive bypass signaling mechanisms that drive resistance to targeted therapy.Methods Six primary PGOs were treated with nine FDA-approved SMIs selected for their blood–brain barrier permeability and ability to target key GB driver genes. Drug sensitivity was assessed by cell viability measurements and IC₅₀ determination. To identify compensatory signaling mechanisms, kinase activity profiling was performed following monotherapy treatment.Results Although inhibition of downstream effector proteins reduced cell viability more effectively (IC₅₀: 70 nM–1 μM) than inhibition of upstream receptor tyrosine kinases (IC₅₀: 1–15 μM), residual proliferation persisted in all PGOs. Kinase profiling revealed compensatory pathway activation following monotherapy, enabling the identification of effective SMI combinations. The most prominent combination targeted glycogen synthase kinase-3 (GSK-3) and mitogen-activated protein kinase kinase (MEK) using CHIR99021 and trametinib, respectively.Conclusion These findings demonstrate that adaptive bypass signaling limits single-agent SMI efficacy in GB. PGO-based kinase profiling enables the identification of resistance mechanisms and rational combination therapies, supporting its application in personalized treatment development.
ASF1B is a critical molecular chaperone for histones H3 and H4 and functions as a core regulator of chromatin assembly, DNA replication, and repair. In recent years, multiple studies have revealed that ASF1B is abnormally overexpressed in various malignant tumors and is correlated with disease progression and poor prognosis, demonstrating its potential as a prognostic biomarker across different cancer types. ASF1B drives tumor cell proliferation, metastasis, treatment resistance, and immune evasion through multiple mechanisms, including direct regulation of the cell cycle, participation in DNA damage repair, and remodeling of the tumor immune microenvironment. Besides, its potential role in non-cancerous diseases has also begun to attract attention. This article systematically reviews the biological characteristics of ASF1B, its expression patterns and functional mechanisms in disease, and explores its translational clinical prospects as a diagnostic marker and therapeutic target, aiming to provide new insights for the precision treatment of related diseases.
Objective Triple-negative breast cancer (TNBC) lacks effective therapeutics in clinical practice. Sorting nexin 10 (SNX10) plays essential roles in various cancers, and the role of SNX10 in TNBC remains unknown. This study investigated the role and action mechanism of SNX10 in TNBC.Methods Using the Kaplan–Meier Plotter database and bc-GenExMiner database to analyze the SNX10 expression and clinical significance. Functional assays, including MTT, colony formation, transwell assays, and xenograft experiments, were used to evaluate the role of SNX10 in TNBC. The GeneChip PrimeView Human Gene Expression Array was used to determine the downstream targets and pathways. Cholesterol levels and the expression of enriched cholesterol synthesis genes were detected by Filipin assay, RT-PCR, and Western Blot. The relationship of SNX10 and cholesterol biosynthesis was confirmed using CO-IP and immunofluorescence staining assays.Results SNX10 is positively related to poor prognosis of breast cancer and markedly up-regulated in TNBC. Knockdown of SNX10 suppressed cell proliferation, migration, and invasion, and slowed the tumor growth in vivo. Mechanistically, SNX10 positively regulates the content and distribution of cellular cholesterol, as does the expression of enriched cholesterol synthesis genes, and SNX10 interacts with SREBP2 and prolongs its half-life. Blocking with lovastatin, cholesterol, or siSREBP2 reversed these effects caused by altering SNX10 in TNBC cells in vitro.Conclusion SNX10 promoted TNBC progression through the regulation of cholesterol biosynthesis, which was mediated by interaction with SREBP2 and maintenance of its stability. SNX10 may be an effective therapeutic target for TNBC, and our study provides new insights into therapeutic strategies.
Background Reliable biomarkers for predicting neoadjuvant chemotherapy (NAC) response in triple-negative breast cancer (TNBC) remain limited. We explored whether RecurIndex-derived molecular features were associated with total pathological complete response (tpCR).Methods Seventy-four patients with TNBC treated with dose-dense NAC were analyzed. Associations between RecurIndex risk scores, 18 core genes, and tpCR were assessed using logistic regression and ROC analyses. Clinical–molecular models were internally validated by bootstrap resampling. Public single-cell RNA-seq data were used for biological contextualization.Results Twenty-nine patients (39.2%) achieved tpCR. The distant recurrence score, was significantly associated with tpCR. OBSL1, BLM, and CCR1 were identified as candidate tpCR-associated genes. The model combining OBSL1, BLM, and clinical nodal stage achieved an AUC of 0.838 and an optimism-corrected AUC of 0.799.Conclusions RecurIndex-derived molecular features were associated with tpCR in TNBC. These exploratory findings warrant validation in independent cohorts.
Objective Clear cell renal cell carcinoma (ccRCC) is characterized by marked molecular and metabolic heterogeneity. This study investigated the functional role of ARHGAP40 in ccRCC and examined signaling and metabolic changes associated with ARHGAP40 expression.Methods TCGA-KIRC and DiseaseMeth datasets were used to analyze ARHGAP40 expression and promoter methylation. Gain- and loss-of-function experiments evaluated malignant phenotypes in vitro, and an ARHGAP40-overexpression xenograft model was used to assess tumor growth. Co-immunoprecipitation and RhoA activity assays assessed ARHGAP40-RhoA interaction and RhoA activation, while PI3K/AKT signaling, glutamine metabolism, GSH/GSSG, and ROS levels were examined. Rescue experiments were performed using SC79, RhoA-Q63L, and NAC.Results ARHGAP40 was downregulated in ccRCC and was associated with increased promoter methylation. ARHGAP40 overexpression suppressed cell proliferation, migration, invasion, EMT, and xenograft growth, while promoting apoptosis and G1-phase arrest; ARHGAP40 knockdown produced the opposite effects. Mechanistically, ARHGAP40 was associated with RhoA, and its overexpression was accompanied by reduced RhoA activity and PI3K/AKT phosphorylation. ARHGAP40 overexpression also reduced intracellular glutamine and glutamate levels and net glutamine consumption, decreased the GSH/GSSG ratio, and increased ROS levels. SC79 and RhoA-Q63L partially reversed the biological and redox effects induced by ARHGAP40 overexpression, whereas NAC reversed the redox changes.Conclusion ARHGAP40 acts as a tumor suppressor in ccRCC. Our findings support a functional link between ARHGAP40, RhoA-PI3K/AKT signaling, glutamine-related metabolism, and cellular redox balance.
