Oncogenesis最新文献

{"title":"Non canonical BRCA1 promotes cell survival via modulating PARP13-mediated SEC61G mRNA decay.","authors":"Binghe Sun, Yuting Li, Yue Wu, Cong Wang, Jiawei Zhu, Wanying Zhang, Dake Li, Wancai Que, Guo Chen","doi":"10.1038/s41389-025-00578-x","DOIUrl":"https://doi.org/10.1038/s41389-025-00578-x","url":null,"abstract":"<p><p>BRCA1, a well-known tumor suppressor, maintains genomic integrity by facilitating homologous recombination (HR) repair and protecting DNA replication forks. However, its roles beyond DNA repair and replication remain largely unexplored. Here, we demonstrate that BRCA1 interacts with the RNA-binding protein PARP13 in the cytoplasm of ovarian cancer cells, with DNA damage enhancing this interaction via DNA-PK. Notably, BRCA1/PARP13 association is essential for cell survival but does not influence DNA repair efficacy following DNA damage. Mechanistically, PARP13 binds and destabilizes the mRNA of the endoplasmic reticulum (ER) membrane protein SEC61G. Upon DNA damage, BRCA1 disrupts PARP13-mediated SEC61G mRNA decay, leading to SEC61G upregulation. Elevated SEC61G levels cause calcium leakage from the ER into the cytosol, activating the pro-survival kinase Akt. These findings identify the BRCA1-PARP13-SEC61G axis as a non-canonical DNA damage response (DDR) pathway and highlight mRNA stability and ER calcium signaling as potential therapeutic targets to overcome chemoresistance. The schematic illustrates the mechanism by which non-canonical BRCA1 promotes cell survival through regulating PARP13-mediated SEC61G mRNA decay. Under DNA damage-free conditions (left panel), SEC61G maintains cellular calcium homeostasis between the endoplasmic reticulum and cytosol to support normal physiological functions. Upon DNA damage induction (right panel), enhanced interaction between BRCA1 and PARP13 attenuates the mRNA degradation activity of PARP13 toward SEC61G, leading to upregulated SEC61G protein expression. The aberrant accumulation of SEC61G triggers endoplasmic reticulum calcium leakage, which subsequently activates the AKT signaling pathway to enhance cell survival capacity.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"14 1","pages":"35"},"PeriodicalIF":6.4,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145239283","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigation of lncRNA expression in newly diagnosed multiple myeloma reveals a LINC01432-CELF2 axis as an inhibitor of apoptosis.","authors":"Richa Mishra, Prasanth Thunuguntla, Dhanusha Duraiyan, Alani Perkin, Katelyn Bagwill, Savannah Gonzales, Catheryn Sizemore, Vanessa Brizuela, Jaiyana King, Stephen Daly, Yoon Jae Chang, Mahdote Abebe, Yash Rajana, Kelly Wichmann, Christ Enyan, Shruthi Rangineni, Mark Fiala, Julie Fortier, Reyka Jayasinghe, Mark Schroeder, Li Ding, Ravi Vij, John DiPersio, Jessica Silva-Fisher","doi":"10.1038/s41389-025-00579-w","DOIUrl":"https://doi.org/10.1038/s41389-025-00579-w","url":null,"abstract":"<p><p>Multiple myeloma (MM) is an incurable malignancy of plasma cells, with over 35,000 new cases diagnosed annually in the United States. Despite an expanding arsenal of approved therapies, nearly all patients relapse, and mechanisms underlying disease progression remain poorly understood. In particular, the role of long non-coding RNAs (lncRNAs) in MM progression and treatment response is largely unexplored. To address this gap, we performed transcriptome sequencing of newly diagnosed MM (NDMM) patient samples and compared individuals with short progression-free survival (PFS; <24 months) to those with prolonged PFS (>24 months) following standard first-line therapy. We identified 157 lncRNAs upregulated in patients with short PFS, and prioritized the most significantly upregulated transcript, LINC01432, for functional characterization. CRISPR-mediated knockdown of LINC01432 expression results in upregulation of genes associated with interferon-α/γ responses and increases apoptosis. Targeting LINC01432 with locked nucleic acid antisense oligonucleotides also induces apoptosis, which can be rescued by LINC01432 overexpression. Mechanistically, we discovered that LINC01432 binds the RNA-binding protein CELF2 directly. Transcriptomic analysis following depletion of either LINC01432 or CELF2 revealed 108 overlapping target genes, indicating that this lncRNA-protein complex regulates transcriptional programs governing immune activation, stress response, and cell survival. In summary, this study identified lncRNAs associated with NDMM and characterized LINC01432 as a critical regulator of MM cell survival, acting in complex with CELF2 to repress pro-apoptotic and immune response pathways. These findings highlight LINC01432 as a potential therapeutic target for overcoming resistance in MM.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"14 1","pages":"36"},"PeriodicalIF":6.4,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145239313","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GlycoRNAs are abundant in glioma and involved in glioma cell proliferation.","authors":"Benkai Xin, Jiajun Chen, Xin Hu, Jingtong Yang, Xiaoyu Wang, Ziqian Wang, Youzhong Wan, Lin Wang","doi":"10.1038/s41389-025-00570-5","DOIUrl":"10.1038/s41389-025-00570-5","url":null,"abstract":"<p><p>Recent studies have identified glycosylated RNAs (glycoRNAs) as a novel class of biomolecules potentially involved in cancers and immunological diseases. However, their presence and functional roles in glioma remain unexplored. GlycoRNAs were extracted from glioma cells and detected using Ac4ManNAz labeling and Northern blot. Small RNA deep sequencing and qRT-PCR were employed to determine RNA types and content. A sequence-specific RNA-capture magnetic bead system was developed to enrich specific glycoRNAs, such as U2 and U4. Glycan components were analyzed using liquid chromatography-mass spectrometry. CCK-8, adhesion, ki67, TUNEL staining assays were used to evaluate cell viability, adhesion, proliferation and apoptosis. Glioma cells were found to be rich in glycoRNAs, predominantly small RNAs, with U2 and U4 being particularly abundant. These glycoRNAs primarily contained fucosylated and sialylated complex glycans. The depletion of cell-surface glycoRNAs at the observed time point significantly inhibited glioma cell viability and proliferation, without altering cell adhesion or apoptosis levels. This study underscored the significant role of glycoRNAs in glioma proliferation and provided a foundation for further research into their potential as novel biomarkers and therapeutic targets for glioma. Glioma cells U87 and LN229 showed significant enrichment in glycoRNAs, predominantly small RNAs, with U2 and U4 being particularly abundant and specific. Furthermore, these glycoRNAs were found to be modified by multiple glycans, primarily complex, fucosylated, and sialylated structures.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"14 1","pages":"29"},"PeriodicalIF":6.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12484618/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145200520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting pregnane X receptor with a potent agonist-based PROTAC to delay colon cancer relapse.","authors":"Lucile Bansard, Guillaume Laconde, Vanessa Delfosse, Tiphaine Huet, Margaux Ayeul, Emilie Rigal, Quentin Donati, Sabine Gerbal-Chaloin, Martine Daujat-Chavanieu, Luc Brunel, Baptiste Legrand, Alain Chavanieu, Anthony R Martin, Julie Pannequin, William Bourguet, Muriel Amblard, Jean Marc Pascussi","doi":"10.1038/s41389-025-00573-2","DOIUrl":"10.1038/s41389-025-00573-2","url":null,"abstract":"<p><p>Tumor recurrence is frequently attributed to drug-tolerant cancer cells. We previously demonstrated that downregulation of the Pregnane X Receptor (PXR, NR1I2) reduces chemoresistance and prevents colorectal cancer recurrence in xenograft mouse models. However, there is currently a lack of clinically-suitable PXR antagonists. In this study, we report the design and synthesis of a novel PXR agonist-based PROTAC (JMV7048) which promotes polyubiquitination and degradation of the human PXR protein via E3 CRBN ubiquitin ligase and 26S proteasome pathways. JMV7048 selectively degrades PXR in colon carcinoma, hepatoma, and pancreatic cancer cell lines, with no impact on primary human hepatocytes. Notably, JMV7048 reduces PXR protein expression in drug-tolerant colon cancer cells, sensitizing them to chemotherapy and significantly delaying cancer relapse in xenografted nude mice. These findings suggest that PXR-targeting PROTACs may serve as novel therapeutic agents to enhance the sensitivity of chemo-resistant cancer cells to chemotherapy.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"14 1","pages":"34"},"PeriodicalIF":6.4,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12398506/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144963610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A dominant SRCAP truncating mutation promotes squamous cell carcinoma progression.","authors":"Stephenie H Droll, Elena I O Dewar, Celia Xue, Max C Levine, Benny J Zhang, Xiaomin Bao","doi":"10.1038/s41389-025-00576-z","DOIUrl":"10.1038/s41389-025-00576-z","url":null,"abstract":"<p><p>The majority of life-threatening cancers arise from epithelial tissues. These epithelial cancers include cutaneous squamous cell carcinoma (cSCC), the second-most common cancer. cSCC is highly invasive and accounts for an estimated 15,000 deaths each year. We identified SRCAP, a chromatin remodeler that regulates the chromatin occupancy of the histone H2A variant H2A.Z, as a frequently mutated gene in cSCC. Analysis of cSCC mutations in epithelial cancers identified a hotspot truncating mutation in SRCAP, which removes 42% of the protein sequences after amino acid 1879. While SRCAP mutations have been previously connected to the pathogenesis of Floating-Harbor syndrome (FHS), these typically occur downstream, with a hotspot mutation leading to protein truncation after amino acid 2444. We found that expressing the SRCAP-1879 truncation in an HRas-CDK4-driven cSCC model was sufficient to increase proliferation, impair terminal differentiation, and accelerate invasion. Mechanistically, the expression of SRCAP-1879 in primary human keratinocytes was sufficient to dysregulate genes crucial for carcinogenesis (e.g., proliferation, differentiation, and motility) without altering H2A.Z occupancy. In particular, the expression of SRCAP-1879 truncation led to strong induction of the matrix metalloproteinase MMP9 expression level, accompanied by increased keratinocyte cell motility, which was sensitive to matrix metalloprotease inhibition. In contrast, the expression of the SRCAP-FHS truncation did not increase but instead reduced cell motility as well as the expression of MMP9. Taken together, our findings identify a previously under-characterized role of the SRCAP-1879 truncating mutation in promoting multiple aspects of epithelial cancer progression, including invasion, distinct from the well-recognized roles of SRCAP mutations in FHS pathogenesis.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"14 1","pages":"33"},"PeriodicalIF":6.4,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12381255/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144963643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BRG1 inhibits glycolysis by promoting SHP1-mediated dephosphorylation of PKM2 in non-small cell lung cancer.","authors":"Wenli Zhan, Haokun Zhang, Xiaowei She, Genshan Zhang, Jiakun Zhang, Xuelai Luo, Haijie Li, Jingqin Lan","doi":"10.1038/s41389-025-00577-y","DOIUrl":"10.1038/s41389-025-00577-y","url":null,"abstract":"<p><p>Glucose metabolic reprogramming serves as a regulatory mechanism to support tumor growth. Here, we identified that BRG1, a subunit of the SWI/SNF chromatin remodeling complex encoded by SMARCA4, can inhibit the glycolysis and proliferation of non-small cell lung cancer (NSCLC) cells. Mechanistically, BRG1 promotes the interaction between SHP1 and PKM2, which affects the subcellular localization and pyruvate kinase activity of PKM2 by reducing its phosphorylation at tyrosine 105 and facilitating PKM2 tetramer formation. Thus, we explored a novel biological function of BRG1 in NSCLC, elucidated the impact of BRG1 on glucose metabolism, and provided insights for clinical strategies targeting tumors with this genetic mutation.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"14 1","pages":"32"},"PeriodicalIF":6.4,"publicationDate":"2025-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12374985/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144963547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Peroxisomal lipid metabolism inhibits Pimozide-induced cancer cell death by regulating ATP homeostasis.","authors":"Zihang Pan, Fazhi Yu, Weiyi You, Feng Li, Fengjuan Cui, Jing Guo, Zhenye Yang","doi":"10.1038/s41389-025-00575-0","DOIUrl":"10.1038/s41389-025-00575-0","url":null,"abstract":"<p><p>Antipsychotic drugs have been shown to suppress tumor growth and induce cell death, but their clinical application remains limited. Pimozide, an FDA-approved antipsychotic, holds significant potential for cancer treatment. However, the mechanisms underlying tumor cell responses to Pimozide remain unclear. In this study, we identify a critical role for peroxisomes in mediating tumor cell resistance to Pimozide. Our findings demonstrate that Pimozide increases peroxisome numbers and that peroxisomal deficiency significantly enhances Pimozide-induced cell death. We show that peroxisomes mitigate Pimozide-induced apoptosis primarily through fatty acid oxidation and ether lipid synthesis, rather than reactive oxygen species (ROS) metabolism. Moreover, Pimozide treatment upregulates peroxisomal lipid-metabolizing enzymes in tumor cells. As key metabolic hubs interconnected with mitochondrial metabolism, peroxisomes support energy homeostasis, thereby preventing Pimozide-induced cell death. These findings underscore the importance of peroxisomes in maintaining mitochondrial morphology and cellular energy homeostasis, offering novel insights into the potential therapeutic applications of Pimozide in cancer treatment.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"14 1","pages":"31"},"PeriodicalIF":6.4,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12371041/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144963626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting macrophage migration inhibitory factor as a potential therapeutic strategy in colorectal cancer.","authors":"Kim Lucia Schneider, Luisa Claus, Richard Bucala, Ramona Schulz-Heddergott","doi":"10.1038/s41389-025-00572-3","DOIUrl":"10.1038/s41389-025-00572-3","url":null,"abstract":"<p><p>Survival rates for patients with late-stage colorectal cancer (CRC) remain low due to limited efficacy of current therapeutic regimens. To overcome these challenges, novel drug targets are urgently needed. Macrophage migration inhibitory factor (MIF), an upstream immunoregulatory cytokine, has emerged as a potential target due to its multifaceted role in cancer pathogenesis. During tumorigenesis, MIF protein levels are often elevated in tumor cells through chaperone-mediated stabilization. Although several in vivo studies have implicated MIF in tumor initiation and progression, its role in sustaining established tumors, particularly when derived from epithelial tumor cells, remained unclear. Using a constitutive Mif knockout mouse model, we previously demonstrated that MIF is required for CRC development. Now, we expanded our experimental CRC model towards a more therapeutic rationale. We hypothesized that epithelial-derived MIF is essential for tumor maintenance and might serve as a possible cancer drug target. Therefore, we depleted epithelial MIF during late-stage CRC tumorigenesis in two genetically-engineered and chemically-induced murine CRC models. Our proof-of-principle study reveals that Mif depletion in epithelial tumor cells attenuates cancer maintenance in both CRC models, coinciding with reduced macrophage recruitment and angiogenesis. Our data highlight the potential utility of targeting MIF in CRC patients for therapeutic benefit.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"14 1","pages":"30"},"PeriodicalIF":6.4,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12368102/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144963553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of LDHB triggers DNA damage and increases cisplatin sensitivity in pleural mesothelioma.","authors":"Yantang Lin, Christelle Dubey, Tereza Losmanova, Samuel Oevgü Yasmin, Jean-Louis Reymond, Ren-Wang Peng, Haibin Deng, Patrick Dorn, Thomas Michael Marti","doi":"10.1038/s41389-025-00571-4","DOIUrl":"10.1038/s41389-025-00571-4","url":null,"abstract":"<p><p>Pleural mesothelioma (PM) is an aggressive, asbestos-linked cancer with limited treatment options and a poor prognosis. Lactate dehydrogenase B (LDHB) converts lactate to pyruvate, and its silencing reduces mitochondrial metabolism, particularly nucleotide synthesis. However, whether and a role of LDHB in PM is unclear. This study aimed to investigate the effects of silencing LDHB in PM cells and their response to chemotherapy. LDHB was silenced using siRNA transfection and inducible shRNA constructs. Proliferation, colony formation, and cell viability were assessed, while DNA damage was analyzed through ɣH2AX levels. Compared to normal mesothelial cells, LDHB was highly expressed in PM cell lines. LDHB inhibition significantly reduced proliferation, cell viability, and colony formation, indicating its crucial role in PM cells. Additionally, LDHB silencing significantly increased nuclear DNA damage accumulation as indicated by elevated ɣH2AX levels, which was reversed by nucleotide supplementation. In vivo, LDHB inhibition reduced tumor growth and enhanced cisplatin's therapeutic efficacy. LDHB silencing increased ɣH2AX levels, which were further elevated with cisplatin treatment. Our results highlight LDHB as a novel therapeutic target in PM, where its inhibition induces DNA damage and improves the efficacy of cisplatin therapy.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"14 1","pages":"28"},"PeriodicalIF":6.4,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12340043/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144822106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel CDK2/CDK9 inhibitor fadraciclib targets cell survival and DNA damage pathways and synergizes with encorafenib in human colorectal cancer cells with BRAF(V600E).","authors":"Md Mohiuddin, Vanda Póvoa, Rita Fior, Frank A Sinicrope","doi":"10.1038/s41389-025-00574-1","DOIUrl":"10.1038/s41389-025-00574-1","url":null,"abstract":"<p><p>The oncogenic BRAF(V600E) mutation activates the ERK1/2 pathway and is detected in 10% of human colorectal cancers (CRCs) where it is associated with poor prognosis. Inhibitors of BRAF have shown only modest efficacy in patients with CRC due to intrinsic drug resistance. We studied the CDK2/CDK9 inhibitor, fadraciclib, alone and in combination with the BRAF inhibitor encorafenib in isogenic human RKO CRC cells with two, one, or no BRAF^V600E alleles (RKO^+/+, A19^+/-, T29^-/-) and in BRAF wild-type HCT-116 cells, including Bax knockout HCT-116^Bax-/- cells. Treatment with fadraciclib was shown to suppress MCL-1 and phospho-MCL-1 (Ser64), induce a Bax-dependent apoptosis, and inhibit colony formation in a BRAF gene dose-dependent manner. Fadraciclib decreased phosphorylation of RNA polymerase II, indicating suppression of RNA transcription. The tumor growth inhibitory effect of fadraciclib plus encorafenib was synergistic. Fadraciclib decreased Rb phosphorylation, inhibited cell cycle progression, and promoted DNA damage as evidenced by cleavage of PARP, increased pH2AX (ser139), and activation of p53. In RKO^+/+ versus A19^+/- or T29^-/- cells, drug treatment was associated with greater suppression of p-Rb and inhibition of apoptosis and the cell cycle. In a zebrafish xenograft model, fadraciclib plus encorafenib significantly reduced tumor size, concurrent with increased caspase-3 activation. In human CRCs, BRAF mutation was associated with overexpression of CDK2, and CDK9 overexpression was associated with worse patient survival. In conclusion, fadraciclib depletes MCL-1 to potentiate apoptosis and, combined with encorafenib, synergistically suppresses tumor cell growth in a BRAF^V600E gene dose-dependent manner. These data suggest a novel therapeutic strategy in CRCs with BRAF^V600E.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"14 1","pages":"27"},"PeriodicalIF":6.4,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12329046/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144794944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}