Molecular Oncology最新文献

The spindle assembly checkpoint (SAC) delays the metaphase-to-anaphase transition. Aurora kinase A (AURKA) inactivation has been shown to cause premature exit from mitosis in the presence of an unsatisfied SAC. We report for the first time that centromeric AURKA interacts with survivin during prometaphase. Notably, depleting or inhibiting AURKA activity at this stage causes mislocalisation of the CPC and BubR1, which compromises the SAC and can lead to mitotic slippage. Furthermore, we show that AURKA binds directly to the BIR domain of survivin at a position distinct from AURKB and indirectly to it via its C terminus. We find the interaction peaks during prometaphase but persists into late mitosis. Importantly, we demonstrate that cells with high levels of survivin are particularly vulnerable to mitotic slippage induced by the AURKA inhibitor, MLN8237/ Alisertib. Alisertib enables both normal and transformed cells with high levels of survivin to activate the APC/C prematurely, as observed by the destruction of cyclin B and securin. Thus, a high expression of survivin can alter cell fate decisions at mitosis and lead to genetic instability, a key hallmark in cancer.

CDK11 is a cyclin-dependent kinase with a role in transcription and RNA splicing and represents a potential target for cancer treatment. We show that blocking CDK11 activity with the OTS964 inhibitor causes p53 stabilisation through MDM2 downregulation. Under these conditions, p53 activates the expression of its downstream effector CDKN1A (p21^WAF1), produced in two isoforms, the canonical p21^C and the recently described p21^L. We compared the ability of both isoforms to block proliferation and showed that p21^L partially lost its inhibitory potential, likely due to the missing cyclin-binding Cy2 and PCNA-interacting motifs and its cytoplasmic localisation. We identified the epitopes of four p21^WAF1 antibodies using phage display to determine isoform specificity. Moreover, we show that the trigger for p21^L induction is inhibition of the spliceosomal protein SF3B1. CDK11 activates SF3B1 by phosphorylation, and inhibition of either SF3B1 or CDK11 induces p21^L. We discovered an isoform similar to human p21^L in murine cells, suggesting evolutionary conservation of CDKN1A alternative splicing. Our results uncover an unknown link between RNA splicing and proliferation control involving a novel isoform of a key cell cycle inhibitor.

Advanced urothelial carcinoma (UC) requires new therapeutics beyond chemo- and immunotherapies. Clinical trials with PARP inhibitors (PARPi), particularly in Cisplatin-treated UC, yielded limited response. Biomarker-based patient selection (apart from BRCAness) or combination treatment may increase efficacy. To identify the most suitable PARPi for UC, we compared Olaparib with Talazoparib. RNA sequencing of PARPi-treated UC lines revealed few common targets and a different impact on immune response. By analysis of experimental and public clinical data, we identified new UC-specific PARPi response predictors SLFN5, SLFN11, and OAS1. We investigated a new combination treatment using PLX51107, an epigenetic BET protein inhibitor, to increase PARPi efficacy. The Talazoparib + PLX51107 combination had a strong synergistic impact on UC cells and organoids, including Cisplatin-resistant cells, allowing dose reduction to spare benign cells. Mechanisms of synergism targeted homologous recombination repair, DNA replication, and apoptosis regulation. In conclusion, we suggest Talazoparib treatment of UC to be highly efficacious on all models examined when combined with PLX51107. This new combination treatment allows efficient application of PARPi Talazoparib to all UC patients, independent of Cisplatin pretreatment and genetic BRCAness.

Low-dose computed tomography (LDCT) screening is increasingly used for early lung cancer detection targeted to high-risk populations. Quantifying overdiagnosis, its potential harms, and economic consequences is important. We assessed the magnitude, harms, and economic impact of lung cancer overdiagnosis from LDCT screening in high-risk populations. We synthesized evidence from eight randomized trials involving 84,660 participants. LDCT may increase overdiagnosis compared to no screening (relative risk [RR] 1.05; 222 additional cases per 100 000 people screened; low certainty). Compared to chest x-ray (CXR), LDCT likely slightly increases overdiagnosis (RR 1.01; 63 additional cases per 100 000 people screened; moderate certainty). The proportion of overdiagnosed cancers is 0.07 (7000 more lung cancers overdiagnosed per 100 000 lung cancers detected; low certainty) when compared to no screening, and 0.01 compared to CXR (1000 more lung cancers overdiagnosed per 100 000 lung cancers detected; moderate certainty). In terms of cost, LDCT resulted in an additional societal burden of €2,026,422.00 per 100 000 individuals screened compared to no screening. The magnitude of overdiagnosis in LDCT screening is likely low compared to CXR.

Metabolic dysfunction-associated steatohepatitis (MASH) is emerging as a major driver of hepatocellular carcinoma (HCC). Crouchet et al. identify PRDX2 as a key regulator linking oxidative stress, metabolic imbalance, and oncogenic signaling. Across multiple in vivo and in vitro models, PRDX2 inhibition restores metabolic homeostasis, reduces tumor initiation, and selectively impairs HCC cell survival. These findings highlight PRDX2 as a promising biomarker and hepatocyte-directed target for chemoprevention, emphasizing the importance of the interplay between metabolism and liver cancer development.

Cervical cancer is highly prevalent in India, with most cases being diagnosed at advanced stages. Despite the standard concurrent chemoradiotherapy (CCRT), 30-40% of patients' experience treatment failure, underscoring the need for improved therapeutic strategies. Understanding resistance mechanisms and identifying predictive biomarkers are crucial to improve treatment efficacy and enable personalized medicine. We conducted a comprehensive genomic and proteomic analysis to identify molecular signatures associated with CCRT. We identified recurrent mutations in phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA) and histone-lysine N-methyltransferase 2D (KMT2D), with mutation signature analysis revealing a prevalent DNA dC- > dU-editing enzyme, APOBEC mutagenesis signature. Distinct genomic alterations, including epidermal growth factor receptor (EGFR) amplification and serine/threonine kinase 11 (STK11) deletion, were exclusively observed in the chemoradiation-resistant cohort. Proteomic analysis identified 73 significantly dysregulated proteins, with syntaxin-3 (STX3), SERPINB7, lipopolysaccharide-binding protein (LBP), EMILIN2, and ribosyldihydronicotinamide dehydrogenase (quinone) (NQO2) being the top five upregulated proteins. Integrative pathway analysis highlighted an active DNA repair pathway in the resistant cohort. This study presents the first proteogenomic profiling of cervical cancer in the Indian population, linking molecular alterations to CCRT response. STK11 and STX3 emerged as predictive biomarkers for poor response, whereas EGFR presents as a promising therapeutic target in the resistant group.

Development of chimeric antigen receptor T-cell therapy has revolutionized the treatment of B-cell malignancies, although challenges such as antigen escape and tumor heterogeneity often decrease treatment success. Modular CARs targeting multiple antigens have been proposed as an interesting solution to address these challenges by reducing the likelihood of tumor cells evading treatment through the loss of a single antigen. In this study, we present a new modular CAR platform, termed CARtein, which takes advantage of intein interactions to jointly target CD19 and CD20 antigens. We demonstrate that the CARtein system, which features a universal CAR signaling backbone that covalently binds to specific scFv-intein recognition partners, generates fully active CARs. Functionality was validated using Raji cells and K562 cells expressing CD19 and/or CD20, observing significant T cell activation through NFAT and NFκB promoter activity and CD69 upregulation. Overall, our study lays the foundation for the establishment of a new way to target multiple antigens through a universal and inert CAR backbone with highly specific activation.

Mismatch repair-proficient (pMMR) colorectal cancers (CRC) have long been considered nonresponsive to immune checkpoint blockade (ICB), in contrast to their mismatch repair-deficient (dMMR) counterparts. Recent evidence indicates that neoadjuvant immunotherapy can be used to treat pMMR CRC before surgery, potentially reducing postoperative relapse. Tan et al. report results from the NICHE-2 trial, which achieved a 26% response rate in early-stage pMMR colon cancer (CC) patients. Molecular studies show that despite low tumor mutational burden (TMB), responders exhibit higher chromosomal instability (CIN), TP53 mutations, and enrichment of proliferative and cell-cycle signatures, associated with higher density of Ki-67⁺ tumor and CD8⁺ T cells. In contrast, nonresponders display metabolic and stromal reprogramming, enhanced TGF-β signaling, and immune exclusion. Circulating tumor DNA (ctDNA) clearance correlated with pathological response and long-term disease-free survival postsurgery. While the biological and molecular determinants underlying the response rates observed in the NICHE-2 trial remain to be fully elucidated, the work by Tan et al. suggests that biomarker-guided neoadjuvant immunotherapy could represent a valuable strategy to achieve pathological responses in early-stage pMMR CC, despite its clinical relevance requiring further evaluation.

Medulloblastoma (MB) is a brain tumor for which current treatments cause serious side effects and are not curative for all patients, highlighting the need for more effective and brain-protecting therapies. Recently, we combined phosphoinositide 3-kinase (PI3K) inhibitor (BYL719), fibroblast growth factor receptor (FGFR) inhibitor (JNJ-42756493) and cyclin-dependent kinase (CDK)4/6 inhibitor (PD-0332991) in MB cell lines, and discovered synergistic effects. In the current study, we investigate the most efficient therapies in a normal/tumorigenic neural stem cell model. A sonic hedgehog (SHH)-MB model, including a Gorlin syndrome patient neuroepithelial stem cell line (NES) and its tumor derivative (tNES), was used to evaluate single and combined treatments of PI3K, AKT, FGFR, and CDK4/6 inhibitors (BYL719, AZD5363, JNJ-42756493, and PD-0332991, respectively). Effects on viability, cell confluence and apoptosis were tested on NES and tNES cells cultured as 2D monolayers and 3D spheroids. We found that 2D tNES cells were generally more sensitive to the inhibitory effects of both single and combination treatments compared to 2D NES cells. In the 3D setting, all single drugs were more effective against tNES than NES, except for JNJ-42756493, which showed the opposite trend. Drug combinations in 3D cultures generally resulted in synergistic or additive effects on cell viability in NES and tNES. This study illustrates that single and combined administrations of PI3K, FGFR, CDK4/6, and AKT inhibitors in a NES/tNES model have dose-dependent and additive/synergistic anti-MB activity impacting tumor growth. Their effects on tNES cells were generally more pronounced than on NES; however, the difference in proliferative capacity between the cells should be considered.

To explore the immune microenvironment of RAS-mutated (RASmt) microsatellite stable (MSS) colon cancer (CC), we retrospectively performed whole exome sequencing, RNA sequencing, and robust digital pathology analyses and studied immune markers in a cohort of 161 patients treated with standard-of-care therapies with early stage disease (both fresh frozen and formalin-fixed paraffin-embedded [FFPE] samples) or 121 patients with metastatic setting (primary tumor FFPE samples). Only a small proportion of cases exhibited a highly infiltrated immune microenvironment, with a strong association between Immunoscore^® (IS)-high (13% of the samples) and Tumor Lymphocytes Infiltrating Score (TuLIS)-high scores (25% of the samples). Immunoscore Immune-Checkpoint (ISIC)-high tumors (52% of the samples) shared a similar microenvironment composition to IS-high and TuLIS-like high tumors and displayed higher mutational burdens than ISIC-low tumors. In conclusion, a substantial proportion of MSS RASmt CCs exhibit high ISIC scores, meriting evaluation in prospective trials of immunotherapy-based combination regimens.