Translational Oncology最新文献

{"title":"Expression of MASTL (Greatwall) associates with good prognosis and response to radiotherapy in pharyngeal squamous cell carcinoma","authors":"Esperanza Pozo-Agundo ,&nbsp;Miguel Álvarez-González ,&nbsp;Israel Rivera-García ,&nbsp;Vanessa García-de-la-Fuente ,&nbsp;Alba de Martino ,&nbsp;Juan Ramón Tejedor ,&nbsp;Juan Carlos de Vicente ,&nbsp;Juan P. Rodrigo ,&nbsp;Juana M. García-Pedrero ,&nbsp;Mónica Álvarez-Fernández","doi":"10.1016/j.tranon.2025.102417","DOIUrl":"10.1016/j.tranon.2025.102417","url":null,"abstract":"<div><div>Head and neck squamous cell carcinomas (HNSCCs) are highly heterogeneous in both disease progression and treatment outcome, with hardly any molecular biomarker in clinical practice. Thus, the aim of this study was to investigate the potential prognostic and predictive value of MASTL/Greatwall, a mitotic kinase also involved in PI3K-mTOR signaling and the DNA damage response, in HNSCC.</div><div>MASTL expression was evaluated by immunohistochemistry in a cohort of 346 surgically treated HPV-negative pharyngeal and laryngeal squamous cell carcinoma patients, as well as in pre-treatment biopsies from a separate cohort of 64 patients treated with induction chemotherapy (ICT). In addition, MASTL mRNA expression was analyzed in 135 patients from The Cancer Genome Atlas (TCGA) database.</div><div>High MASTL expression was significantly associated with improved disease-specific survival (DSS) (<em>P</em> = 0.029), specifically in well-differentiated pharyngeal squamous cell carcinoma (PSCC) tumors (<em>P</em> = 0.002). Notably, this association was restricted to patients who received adjuvant radiotherapy (RT) (<em>P</em> = 0.009). Consistently, a similar correlation was found at the mRNA level in PSCC tumors from the TCGA dataset. Moreover, the combined expression of MASTL and p21 was significantly associated with better DSS, specifically among patients receiving RT (<em>P</em> = 0.014). Multivariate Cox regression analysis further confirmed that high MASTL expression was independently associated with favorable prognosis in patients who received post-operative RT (HR= 0.65; 95 % CI: 0.45–0.94; <em>P</em> = 0.021).</div><div>Collectively, these findings unprecedentedly revealed the association between high MASTL expression and favorable outcome in advanced HPV-negative PSCC, in marked contrast to previous reports in other tumor types. Importantly, MASTL expression emerges as an independent predictor of good prognosis in RT-treated PSCC patients.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"58 ","pages":"Article 102417"},"PeriodicalIF":5.0,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144089752","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":"FRESCO–2 trial and fruquintinib: A clearer picture of the control arm","authors":"Sruthi Ranganathan ,&nbsp;Alyson Haslam ,&nbsp;Timothée Olivier ,&nbsp;Vinay Prasad","doi":"10.1016/j.tranon.2025.102392","DOIUrl":"10.1016/j.tranon.2025.102392","url":null,"abstract":"<div><div>Though vascular endothelial growth factor receptor (VEGFR)-targeting drugs have been approved in the past and are known for their potential off-site action, fruquintinib is a possible new, specific inhibitor of VEGFR-1, 2, and 3. The US Food and Drug Administration (FDA) recently approved fruquintinib based on the FRESCO-2 trial results. However, the FRESCO-2 trial is potentially problematic given the suboptimal choice of placebo in the trial, and the poor cost-effectiveness of fruquintinib. Firstly, we argue that fruquintinib should have been tested against regorafenib, and only offered a moderate benefit despite being tested against a suboptimal placebo. Secondly, fruquintinib is likely cost ineffective (measured in quality-adjusted life years (QALY)), with a crude estimation placing its value over a million USD per QALY. Lastly, we show that the use of a suboptimal placebo is unfortunately not new.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"58 ","pages":"Article 102392"},"PeriodicalIF":5.0,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144089751","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":"Downregulation of PIP4K2C inhibits the breast cancer cell proliferation, migration and invasion","authors":"Yue Jin ,&nbsp;Jian Xue ,&nbsp;Xinyue Li ,&nbsp;Xiaoli Zhong","doi":"10.1016/j.tranon.2025.102420","DOIUrl":"10.1016/j.tranon.2025.102420","url":null,"abstract":"<div><div>Phosphoinositide signaling pathway has garnered significant attention in recent years due to its implication in metabolic alterations associated with various human diseases, including breast cancer. Phosphatidylinositol-5-phosphate 4-kinase (PIP4K) catalyzes the phosphorylation of phosphatidylinositol-5-phosphate (PI5P) to produce phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2), a lipid that regulates signaling pathways associated with cancer cell growth and metastasis. In breast cancer, PIP4Ks, especially PIP4Kα and PIP4Kβ, have emerged as a significant player, with their dysregulation linked to tumor progression and poor prognosis. However, the role of PIP4Kγ (encoded by <em>PIP4K2C</em>), the other isoform of PIP4K family, remains largely uncharted in breast cancer. Here, we demonstrated that the expression of <em>PIP4K2C</em> is upregulated in breast cancer tissues opposed to the normal tissue utilizing the GTEx and the TCGA public database. The elevation of PIP4K2C expression is further confirmed in the breast cancer cell lines and tissues. Downregulated expression of <em>PIP4K2C</em> by siRNA lowered the subcellular PI(4,5)P2 and suppressed proliferation, migration and invasion of MDA-MB-468, MCF7 breast cancer cell lines. Our research substantiates PIP4K2C as a promising diagnostic and therapeutic biomarker for breast cancer, warranting further investigation into its mechanistic and clinical implications.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"57 ","pages":"Article 102420"},"PeriodicalIF":5.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144083801","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":"Targeting EPAS-1/HIF-2α Pathway to Address Endocrine Resistance in Luminal A Type Breast Cancer","authors":"Enzhi Luo,&nbsp;Seongmin Lee,&nbsp;Neeraj manvi agarwal,&nbsp;Junjeong Choi","doi":"10.1016/j.tranon.2025.102415","DOIUrl":"10.1016/j.tranon.2025.102415","url":null,"abstract":"<div><h3>Background</h3><div>Tamoxifen is most often used as the first treatment for luminal A breast cancer; however, one-third of the patients are resistant to it. Numerous studies have shown that hypoxia contributes to drug resistance and is related to poor clinical outcomes. Despite this, little is known regarding the key hypoxic mediators involved in tamoxifen resistance.</div></div><div><h3>Methods</h3><div>We performed a comprehensive multi-omics analysis using publicly available transcriptomics and whole-exome sequencing data from tamoxifen-sensitive and tamoxifen-resistant luminal A breast cancer patient samples. EPAS1 was identified as a key hypoxic mediator linked to endocrine resistance in luminal A breast cancer. In vitro assays, including Western blotting, hypoxia detection assays, and CCK8 assays, were conducted to validate the association between EPAS1 expression and tamoxifen resistance in cell lines. Additionally, we tested the effect of PT2977 (Belzutifan), an EPAS1 inhibitor, as a potential treatment for tamoxifen resistance using tamoxifen-resistant and control cells, followed by validation in xenograft models of tamoxifen-resistant tumours.</div></div><div><h3>Results</h3><div>Patient and cell line data revealed that EPAS1 is significantly upregulated in tamoxifen-resistant luminal A breast cancer, which is associated with poor survival outcomes and an altered tumour microenvironment. Further investigation using tamoxifen-resistant cell lines confirmed elevated EPAS1 expression levels. In vitro treatment with the EPAS1 inhibitor PT2977 resulted in a significant decrease in cell viability and modulated hypoxia-related pathways, indicating a potential therapeutic effect. Furthermore, in vivo studies showed that PT2977 reduced the growth of tamoxifen-resistant cells under the experimental conditions used.</div></div><div><h3>Conclusion</h3><div>This study suggests that PT2977, by targeting the hypoxic gene EPAS1, has the potential to inhibit the growth of tamoxifen-resistant luminal A breast cancer. However, while PT2977 demonstrated effectiveness in reducing tumour growth under the experimental conditions used, further studies are necessary to evaluate its role in overcoming hormone resistance and to explore its therapeutic applicability in broader clinical settings and other cancer subtypes.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"57 ","pages":"Article 102415"},"PeriodicalIF":5.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144090270","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":"Dap10 co-stimulation enhances the anti-HCC efficacy of NKp30 chimeric antigen receptor T cells","authors":"JieYu Li ,&nbsp;LiMei Chen ,&nbsp;MingShui Chen ,&nbsp;Miao Lin ,&nbsp;Zineng Xie ,&nbsp;HuiLing Wu ,&nbsp;ZhiFeng Zhou ,&nbsp;WanSong Lin","doi":"10.1016/j.tranon.2025.102425","DOIUrl":"10.1016/j.tranon.2025.102425","url":null,"abstract":"<div><div>Chimeric antigen receptor (CAR) T-cell immunotherapy has made significant breakthroughs in the treatment of relapsed or refractory hematologic malignancies, but its efficacy in solid tumors remains limited. In this study, we developed a chimeric NKp30 (chNKp30) receptor whose ligand, B7H6, is often up-regulated in various tumor cells and sparsely expressed in healthy cells. Introduction of the cytoplasmic structural domain of dnax-activating protein 10 (DAP10) into CAR resulted in chNKp30-Dap10 CAR-T cells that showed superior cell proliferation, activation, and apoptosis inhibition after antigenic stimulation compared with conventional chNKp30-CD28 and chNKp30-Wt CAR-T cells lacking any structural domains, along with inducing a central memory T cell phenotype, whereas chNKp30-CD28 and chNKp30-Wt triggered an effector memory phenotype. In addition, chNKp30-Dap10 T cells secreted higher levels of pro-inflammatory cytokines such as IL-2, IFN-γ, and TNF-α, while chNKp30-CD28 T cells secreted more of the anti-inflammatory cytokine IL-10. In the killing assay, chNKp30-Dap10 T cells demonstrated stronger anti-tumor effects. Similarly, better tumor regression was observed in the hepatocellular carcinoma transplantation tumor model. These findings suggest that B7H6 is an attractive therapeutic target and DAP10 signaling is involved in the functional regulation of CAR-T cells in hepatocellular carcinoma, which may induce preferential cytokine profiling and differentiation for cancer therapy, and that NKp30-Dap10 CAR-T cell therapy offers a potential option for the treatment of hepatocellular carcinoma.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"57 ","pages":"Article 102425"},"PeriodicalIF":5.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144090340","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":"KRAS inhibition reverses chemotherapy resistance promoted by therapy-induced senescence-like in pancreatic ductal adenocarcinoma","authors":"Analia Meilerman Abuelafia ,&nbsp;Patricia Santofimia-Castaño ,&nbsp;Matias Estaras ,&nbsp;Daniel Grasso ,&nbsp;Eduardo Chuluyan ,&nbsp;Gwen Lomberk ,&nbsp;Raul Urrutia ,&nbsp;Nelson Dusetti ,&nbsp;Nicolas Fraunhoffer ,&nbsp;Juan Iovanna","doi":"10.1016/j.tranon.2025.102421","DOIUrl":"10.1016/j.tranon.2025.102421","url":null,"abstract":"<div><h3>Background</h3><div>Emerging evidence suggests that chemotherapy can accumulate senescent-like cells within tumor tissues, a phenomenon linked to therapy resistance. The aim of this study is to analyze the senescence-like state of after-treatment persistent cells associated with KRAS mutational status to offer a therapeutic strategy to target these cells in pancreatic ductal adenocarcinoma (PDAC).</div></div><div><h3>Experimental Design</h3><div>Three commercial cell lines and five patient-derived primary cell cultures with different KRAS statuses were studied following gemcitabine treatment. Senescence-like status was assessed using SA-β-gal, together with cell cycle regulators such as p21. Additionally, KRAS mutations were modulated using MRTX1133 and AMG-510, and the signaling pathways ERK and AKT were analyzed and modulated in vitro. Finally, p21 expression, associated with the senescence-like state, on patient outcomes and treatment response was analyzed in publicly available bulk RNA-seq and single-nucleus datasets.</div></div><div><h3>Results</h3><div>We observed an overexpression of p21 alongside an increase in SA-β-gal signal in response to gemcitabine treatment, indicating the induction of a senescence-like state. Specific inhibition of KRAS G12D or G12C mutations reduced SA-β-gal signal and sensitized PDAC cells to gemcitabine. Moreover, ERK inhibition but not AKT inhibition decreased SA-β-gal signal. Additionally, we characterized p21 expression levels in relation to patient outcomes and found that they are modulated by treatment.</div></div><div><h3>Conclusions</h3><div>This dual-targeted therapeutic strategy holds promises for overcoming the challenges posed by KRAS-driven cancers, particularly in addressing the formidable obstacle of pancreatic cancer.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"57 ","pages":"Article 102421"},"PeriodicalIF":5.0,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144071394","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":"HELQ upregulates PARP1 to drive platinum resistance and predict therapeutic response in ovarian cancer","authors":"Shuran Tan ,&nbsp;Fang Zhu ,&nbsp;Yi Li ,&nbsp;Xinxin Wen ,&nbsp;Siyu Yang ,&nbsp;Zexi Liao ,&nbsp;Xuerui Duan ,&nbsp;Di Xiao ,&nbsp;Yu Zhang","doi":"10.1016/j.tranon.2025.102416","DOIUrl":"10.1016/j.tranon.2025.102416","url":null,"abstract":"<div><div>POLQ-like helicase (HELQ), an evolutionarily conserved 3'-5′ DNA helicase, is markedly overexpressed in platinum-resistant ovarian cancer (OC), which is correlated with a poor prognosis. However, the mechanisms linking HELQ with resistance to platinum-based chemotherapy remain unkonwn. Our study presents both <em>in vitro</em> and <em>in vivo</em> evidence that elevated HELQ expression is linked to increased chemoresistance in OC models, with reduced HELQ levels enhancing their sensitivity to platinum agents. The expression of γH2AX, RPA1 and 53BP1 determined by immunofluorescence and western blot indicated that HELQ could promote platinum-induced DNA damage repair. HELQ was found to promote OC platinum resistance by regulating the expression of poly (ADP-ribose) polymerase 1(PARP1), which could be reversed by PARP1 downregulation. Furthermore, <em>in vitro</em> experiments showed that HELQ overexpression sensitizes OC cells to PARP inhibitors (PARPi). Immunohistochemical analysis indicates that diminished HELQ expression in tumor tissues correlates with disease progression in patients with first-line maintenance therapy with PARPi, whereby higher expression levels predict improved progression-free survival. Notably, we found a positive correlation between PARP1 and HELQ expression. In conclusion, HELQupregulats PARP1 to promote platinum resistance in OC and warrants consideration as an emerging biomarker for monitoring therapeutic responses to chemotherapy and PARPi treatment in ovarian cancer.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"57 ","pages":"Article 102416"},"PeriodicalIF":5.0,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144071392","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":"CD38 contributes to tumor progression and tumor microenvironment reshaping in epithelial ovarian cancer","authors":"Wei Wang ,&nbsp;Xiangnan Liu ,&nbsp;Shengjie Xu,&nbsp;Enci Dai,&nbsp;Yingying Li,&nbsp;Yinping Liu,&nbsp;Liyun Shan,&nbsp;Yanli Li","doi":"10.1016/j.tranon.2025.102414","DOIUrl":"10.1016/j.tranon.2025.102414","url":null,"abstract":"<div><h3>Background</h3><div>Ovarian cancer, ranking fifth in cancer mortality, presents a significant therapeutic challenge. The immunomodulatory functions of CD38in epithelial ovarian cancer (EOC) and its influence on the tumor microenvironment (TME) remain poorly understood.</div></div><div><h3>Methods</h3><div>Public datasets, RT-qPCR and immunohistochemistry (IHC) were used to analyze CD38 expression and clinicopathological features in EOC. Gene manipulation techniques were employed to elucidate its functions, while integrated IHC and bioinformatics were conducted to assess its involvement in immune/stromal infiltration. Immune-related functions of CD38 were explored using GO, KEGG analysis and TIP database. TIDE algorithm was employed to predict the correlation between CD38 and immune checkpoint blocking responsiveness. CD38 inhibitor efficacy was evaluated in an EOC mouse model, with flow cytometry monitoring cellular changes. The involvement of CD38 in the PI3K-AKT and IL-6 signaling pathways was evaluated using RT-qPCR, western blot, and publicly datasets.</div></div><div><h3>Results</h3><div>CD38 is significantly upregulated in EOC, influencing the cell proliferation and metastasis. It regulates the PI3K-AKT and IL-6 signaling pathways, thereby increasing tumor malignancy. CD38 is also upregulated in immune and stromal cells, affecting TME remodeling by facilitating immune cell and CAF infiltration, impeding T cell recognition of tumor cells, and enhancing CAF-tumor cell communication. Additionally, CD38 correlates with multiple immune checkpoint molecules. Notably, CD38 inhibitor therapy inhibited effectively EOC progression and modulates immune responses.</div></div><div><h3>Conclusion</h3><div>Elevated CD38 expression is associated with EOC progression, TME remodeling, and immune response modulation. Thus, CD38 could be a promising target for ovarian cancer immunotherapy.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"57 ","pages":"Article 102414"},"PeriodicalIF":5.0,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144071391","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":"The impact of serpinB3-PD polymorphism on the prognosis of patients with hepatocellular carcinoma","authors":"Pietro Guerra ,&nbsp;Mariagrazia Ruvoletto ,&nbsp;Santina Quarta ,&nbsp;Giulia Boninsegna ,&nbsp;Alessandra Biasiolo ,&nbsp;Silvia Cagnin ,&nbsp;Paolo Angeli ,&nbsp;Patrizia Pontisso ,&nbsp;Andrea Martini","doi":"10.1016/j.tranon.2025.102413","DOIUrl":"10.1016/j.tranon.2025.102413","url":null,"abstract":"<div><h3>Background</h3><div>HCC ranks as the third leading cause of cancer-related death, yet current surveillance strategies miss over one-third of cases at an early stage. SerpinB3-PD (SB3-PD), a polymorphic isoform of a serine-protease inhibitor involved in tumorigenesis and fibrogenesis, has been related to a more rapid cirrhosis decompensation. This study investigates the prognostic role of SB3-PD in patients with HCC.</div></div><div><h3>Methods</h3><div>SB3-PD polymorphism was assessed in 140 patients with HCC, followed up in our outpatient Clinic. Cell invasion analysis was conducted on HepG2 cells either overexpressing the SB3 wild-type (HepG2/SB3WT) or the PD isoform (HepG2/SB3PD). The effect of recombinant SB3-WT or SB3-PD on the production of molecules that impair immunosurveillance was also assessed in the THP-1 monocytic cell line.</div></div><div><h3>Results</h3><div>Patients carrying SB3-PD polymorphism showed worse tumour characteristics, associated with significantly lower survival and SB3-PD was an independent predictor of mortality. HepG2/SB3PD cells had a significantly higher invasion capacity than the HepG2/SB3WT. In THP-1 cells recombinant SB3-PD induced higher levels of PDL1 and IL-13 than SB3-WT.</div></div><div><h3>Conclusion</h3><div>SB3-PD isoform is associated with worse clinical prognosis in patients with HCC. These findings were supported in vitro by increased cellular invasion and higher production of molecules impairing immunosurveillance.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"57 ","pages":"Article 102413"},"PeriodicalIF":5.0,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143936293","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":"The synergy of TPL and selinexor in MLL-R acute myeloid leukemia via Rap1/Raf/MEK pathway-mediated MYC downregulation","authors":"Manman Deng ,&nbsp;Peicui Huang ,&nbsp;Lijuan Wang ,&nbsp;Yuelong Jiang ,&nbsp;Zhenling Guo ,&nbsp;Hongpeng Duan ,&nbsp;Jie Zha ,&nbsp;Haijun Zhao ,&nbsp;Guowei Li ,&nbsp;Bing Xu","doi":"10.1016/j.tranon.2025.102399","DOIUrl":"10.1016/j.tranon.2025.102399","url":null,"abstract":"<div><div>MLL gene rearrangement recurrently occurs in acute myeloid leukemia (MLL-r AML), which is closely associated with chemotherapy insensitivity and unfavorable clinical outcomes. More importantly, there are limited therapeutic options for the management of patients with MLL-r AML, thus necessitating novel effective treatment strategies. In this study, we demonstrated that low doses of triptolide (LD TPL) and the XPO1 inhibitor selinexor exerted synergistic therapeutic effects on poor-outcome MLL-r AML in vitro, ex vivo and in vivo. Induction of mitochondrial outer membrane permeabilization (MOMP) and initiation of the mitochondrial apoptotic pathway were closely involved in the therapeutic synergy of LD TPL in combination with selinexor against MLL-r AML. Mechanistically, MYC downregulation mediated by the Rap1/Raf/MEK/ERK pathway rather than by PI3K/AKT signaling was implicated in the synergistic activity of the combined regimen. In addition, the induction of DNA damage also contributed to the synergistic effects of the combined regimen on MLL-r AML. In summary, our findings suggest that LD TPL in combination with selinexor might represent a promising therapeutic approach for the treatment of MLL-r AML. However, future clinical trials are mandatory to draw a decisive conclusion.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"57 ","pages":"Article 102399"},"PeriodicalIF":5.0,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143942107","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}