Molecular Oncology最新文献

{"title":"ERK1/2 mitogen‐activated protein kinase dimerization is essential for the regulation of cell motility","authors":"Dalia de la Fuente‐Vivas, Vincenzo Cappitelli, Rocío García‐Gómez, Sara Valero‐Díaz, Camilla Amato, Javier Rodriguéz, Santiago Duro‐Sánchez, Alexander von Kriegsheim, Michael Grusch, José Lozano, Joaquín Arribas, Berta Casar, Piero Crespo","doi":"10.1002/1878-0261.13732","DOIUrl":"https://doi.org/10.1002/1878-0261.13732","url":null,"abstract":"ERK1/2 mitogen‐activated protein kinases (ERK) are key regulators of basic cellular processes, including proliferation, survival, and migration. Upon phosphorylation, ERK becomes activated and a portion of it dimerizes. The importance of ERK activation in specific cellular events is generally well documented, but the role played by dimerization is largely unknown. Here, we demonstrate that impeding ERK dimerization precludes cellular movement by interfering with the molecular machinery that executes the rearrangements of the actin cytoskeleton. We also show that a constitutively dimeric ERK mutant can drive cell motility <jats:italic>per se</jats:italic>, demonstrating that ERK dimerization is both necessary and sufficient for inducing cellular migration. Importantly, we unveil that the scaffold protein kinase suppressor of Ras 1 (KSR1) is a critical element for endowing external agonists, acting through tyrosine kinase receptors, with the capacity to induce ERK dimerization and, subsequently, to unleash cellular motion. In agreement, clinical data disclose that high <jats:italic>KSR1</jats:italic> expression levels correlate with greater metastatic potential and adverse evolution of mammary tumors. Overall, our results portray both ERK dimerization and KSR1 as essential factors for the regulation of cell motility and mammary tumor dissemination.","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":"64 1","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142210134","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":"Enhancing immunotherapy through PD‐L1 upregulation: the promising combination of anti‐PD‐L1 plus mTOR inhibitors","authors":"Anna Hernández‐Prat, Alejo Rodriguez‐Vida, Laura Cardona, Mengjuan Qin, Oriol Arpí‐Llucià, Luis Soria‐Jiménez, Sílvia Menendez, Fabricio Gerel Quimis, Miguel Galindo, Edurne Arriola, Marta Salido, Nuria Juanpere‐Rodero, Federico Rojo, Aura Muntasell, Joan Albanell, Ana Rovira, Joaquim Bellmunt","doi":"10.1002/1878-0261.13699","DOIUrl":"https://doi.org/10.1002/1878-0261.13699","url":null,"abstract":"Immune checkpoint inhibitors (ICIs) targeting the programmed cell death protein 1 (PD‐1)/programmed cell death 1 ligand 1 (PD‐L1) pathway have transformed urothelial cancer (UC) therapy. The correlation between PD‐L1 expression and ICI effectiveness is uncertain, leaving the role of PD‐L1 as a predictive marker for ICI efficacy unclear. Among several ways to enhance the efficacy of ICI, trials are exploring combining ICIs with serine/threonine‐protein kinase mTOR (mTOR) inhibitors in different tumor types. The potential interaction between mTOR inhibitors and PD‐L1 expression in UC has not been well characterized. In our study, we investigated how phosphoinositide 3‐kinase (PI3K)/AKT/mTOR pathway inhibitors (TAK‐228, everolimus and TAK‐117) affect PD‐L1 expression and function in preclinical bladder cancer cell models. TAK‐228 increased cell surface levels of glycosylated PD‐L1 in all but one of the seven cell lines, regardless of baseline levels. TAK‐228 promoted the secretion of epidermal growth factor (EGF) and interferon‐β (IFNβ), both linked to PD‐L1 protein induction. Blocking EGF and IFNβ receptors reversed the TAK‐228‐induced PD‐L1 increase. Additionally, TAK‐228 enhanced IFN‐γ‐induced PD‐L1 expression and intracellular HLA‐I levels in some cells. TAK‐228‐treated bladder cancer cells exhibited resistance to the cytotoxic effects of peripheral blood mononuclear cells (PBMCs) and cluster of differentiation 8 (CD8)+ T cells. The addition of an anti‐PD‐L1 antibody diminished this resistance in T24 cells. Increased expression of PD‐L1 under TAK‐228 exposure was confirmed in patient‐derived explants (PDEs) treated <jats:italic>ex vivo</jats:italic>. These preclinical findings suggest that mTOR inhibition with TAK‐228 can increase PD‐L1 levels, potentially impacting the specific immune response against UC cells. This highlights the rationale for exploring the combination of mTOR inhibitors with ICIs in patients with advanced UC.","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":"64 1","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142209992","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 the CLK2/SRSF9 splicing axis in prostate cancer leads to decreased ARV7 expression","authors":"Jasper Van Goubergen, Miroslav Peřina, Florian Handle, Elisa Morales, Anika Kremer, Oliver Schmidt, Glen Kristiansen, Marcus V. Cronauer, Frédéric R. Santer","doi":"10.1002/1878-0261.13728","DOIUrl":"https://doi.org/10.1002/1878-0261.13728","url":null,"abstract":"In advanced prostate cancer (PC), in particular after acquisition of resistance to androgen receptor (AR) signaling inhibitors (ARSI), upregulation of AR splice variants compromises endocrine therapy efficiency. Androgen receptor splice variant‐7 (ARV7) is clinically the most relevant and has a distinct 3′ untranslated region (3′UTR) compared to the AR full‐length variant, suggesting a unique post‐transcriptional regulation. Here, we set out to evaluate the applicability of the <jats:italic>ARV7</jats:italic> 3′UTR as a therapy target. A common single nucleotide polymorphism, rs5918762, was found to affect the splicing rate and thus the expression of <jats:italic>ARV7</jats:italic> in cellular models and patient specimens. Serine/arginine‐rich splicing factor 9 (SRSF9) was found to bind to and increase the inclusion of the cryptic exon 3 of <jats:italic>ARV7</jats:italic> during the splicing process in the alternative C allele of rs5918762. The dual specificity protein kinase CLK2 interferes with the activity of SRSF9 by regulating its expression. Inhibition of the Cdc2‐like kinase (CLK) family by the small molecules cirtuvivint or lorecivivint results in the decreased expression of <jats:italic>ARV7</jats:italic>. Both inhibitors show potent anti‐proliferative effects in enzalutamide‐treated or ‐naive PC models. Thus, targeting aberrant alternative splicing at the 3′UTR of <jats:italic>ARV7</jats:italic> by disturbing the CLK2/SRSF9 axis might be a valuable therapeutic approach in late stage, ARSI‐resistant PC.","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":"10 1","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142210130","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":"KRASG12C‐inhibitor‐based combination therapies for pancreatic cancer: insights from drug screening","authors":"Constanza Tapia Contreras, Jonas Dominik Falke, Dana‐Magdalena Seifert, Carolin Schneider, Lukas Krauß, Xin Fang, Denise Müller, Engin Demirdizen, Melanie Spitzner, Tiago De Oliveira, Christian Schneeweis, Jochen Gaedcke, Silke Kaulfuß, Kimia Mirzakhani, Bernd Wollnik, Karly Conrads, Tim Beißbarth, Gabriela Salinas, Jonas Hügel, Nils Beyer, Sophia Rheinländer, Ulrich Sax, Matthias Wirth, Lena‐Christin Conradi, Maximilian Reichert, Volker Ellenrieder, Philipp Ströbel, Michael Ghadimi, Marian Grade, Dieter Saur, Elisabeth Hessmann, Günter Schneider","doi":"10.1002/1878-0261.13725","DOIUrl":"https://doi.org/10.1002/1878-0261.13725","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) has limited treatment options, emphasizing the urgent need for effective therapies. The predominant driver in PDAC is mutated KRAS proto‐oncogene, <jats:italic>KRA</jats:italic>, present in 90% of patients. The emergence of direct KRAS inhibitors presents a promising avenue for treatment, particularly those targeting the <jats:italic>KRAS</jats:italic><jats:sup><jats:italic>G12C</jats:italic></jats:sup> mutated allele, which show encouraging results in clinical trials. However, the development of resistance necessitates exploring potent combination therapies. Our objective was to identify effective KRAS<jats:sup>G12C</jats:sup>‐inhibitor combination therapies through unbiased drug screening. Results revealed synergistic effects with son of sevenless homolog 1 (SOS1) inhibitors, tyrosine‐protein phosphatase non‐receptor type 11 (PTPN11)/Src homology region 2 domain‐containing phosphatase‐2 (SHP2) inhibitors, and broad‐spectrum multi‐kinase inhibitors. Validation in a novel and unique KRAS<jats:sup>G12C</jats:sup>‐mutated patient‐derived organoid model confirmed the described hits from the screening experiment. Our findings propose strategies to enhance KRAS<jats:sup>G12C</jats:sup>‐inhibitor efficacy, guiding clinical trial design and molecular tumor boards.","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":"105 1","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142210132","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":"Patient-derived acellular ascites fluid affects drug responses in ovarian cancer cell lines through the activation of key signalling pathways.","authors":"Katharina Bischof, Andrea Cremaschi, Lena Eroukhmanoff, Johannes Landskron, Lise-Lotte Flage-Larsen, Alexandra Gade, Line Bjørge, Alfonso Urbanucci, Kjetil Taskén","doi":"10.1002/1878-0261.13726","DOIUrl":"https://doi.org/10.1002/1878-0261.13726","url":null,"abstract":"<p><p>Malignant ascites is commonly produced in advanced epithelial ovarian cancer (EOC) and serves as unique microenvironment for tumour cells. Acellular ascites fluid (AAF) is rich in signalling molecules and has been proposed to play a role in the induction of chemoresistance. Through in vitro testing of drug sensitivity and by assessing intracellular phosphorylation status in response to mono- and combination treatment of five EOC cell lines after incubation with AAFs derived from 20 different patients, we investigated the chemoresistance-inducing potential of ascites. We show that the addition of AAFs to the culture media of EOC cell lines has the potential to induce resistance to standard-of-care drugs (SCDs). We also show that AAFs induce time- and concentration-dependent activation of downstream signalling to signal transducer and activator of transcription 3 (STAT3), and concomitantly altered phosphorylation of mitogen-activated protein kinase kinase (MEK), phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT) and nuclear factor NF-kappa-B (NFκB). Antibodies targeting the interleukin-6 receptor (IL6R) effectively blocked phosphorylation of STAT3 and STAT1. Treatments with SCDs were effective in reducing cell viability in only a third of 30 clinically relevant conditions examined, defined as combinations of drugs, different cell lines and AAFs. Combinations of SCDs and novel therapeutics such as trametinib, fludarabine or rapamycin were superior in another third. Notably, we could nominate effective treatment combinations in almost all conditions except in 4 out of 30 conditions, in which trametinib or fludarabine showed higher efficacy alone. Taken together, our study underscores the importance of the molecular characterisation of individual patients' AAFs and the impact on treatment resistance as providing clinically meaningful information for future precision treatment approaches in EOC.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142154595","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":"Tumor and α-SMA-expressing stromal cells in pancreatic neuroendocrine tumors have a distinct RNA profile depending on tumor grade.","authors":"Helvijs Niedra, Raitis Peculis, Rihards Saksis, Ilona Mandrika, Sofija Vilisova, Jurijs Nazarovs, Austra Breiksa, Aija Gerina, Julie Earl, Ignacio Ruz-Caracuel, Marta Gabriela Rosas, Aldis Pukitis, Natalja Senterjakova, Vita Rovite","doi":"10.1002/1878-0261.13727","DOIUrl":"https://doi.org/10.1002/1878-0261.13727","url":null,"abstract":"<p><p>Alpha-smooth muscle actin (α-SMA) expression in the stroma is linked to the presence of cancer-associated fibroblasts and is known to correlate with worse outcomes in various tumors. In this study, using a GeoMx digital spatial profiling approach, we characterized the gene expression of the tumor and α-SMA-expressing stromal cell compartments in pancreatic neuroendocrine tumors (PanNETs). The profiling was performed on tissues from eight retrospective cases (three grade 1, four grade 2, and one grade 3). Selected regions of interest were segmented geometrically based on tissue morphology and fluorescent signals from synaptophysin and α-SMA markers. The α-SMA-expressing stromal-cell-associated genes were involved in pathways of extracellular matrix modification, whereas, in tumor cells, the gene expression profiles were associated with pathways involved in cell proliferation. The comparison of gene expression profiles across all three PanNET grades revealed that the differences between grades are not only present at the level of the tumor but also in the α-SMA-expressing stromal cells. Furthermore, the tumor cells from regions with a rich presence of adjacent α-SMA-expressing stromal cells revealed an upregulation of matrix metalloproteinase-9 (MMP9) expression in grade 3 tumors. This study provides an in-depth characterization of gene expression profiles in α-SMA-expressing stromal and tumor cells, and outlines potential crosstalk mechanisms.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142154596","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":"Simultaneous detection of eight cancer types using a multiplex droplet digital PCR assay.","authors":"Isabelle Neefs, Nele De Meulenaere, Thomas Vanpoucke, Janah Vandenhoeck, Dieter Peeters, Marc Peeters, Guy Van Camp, Ken Op de Beeck","doi":"10.1002/1878-0261.13708","DOIUrl":"https://doi.org/10.1002/1878-0261.13708","url":null,"abstract":"<p><p>DNA methylation biomarkers have emerged as promising tools for cancer detection. Common methylation patterns across tumor types allow multi-cancer detection. Droplet digital PCR (ddPCR) has gained considerable attention for methylation detection. However, multi-cancer detection using multiple targets in ddPCR has never been performed before. Therefore, we developed a multiplex ddPCR assay for multi-cancer detection. Based on previous data analyses using The Cancer Genome Atlas (TCGA), we selected differentially methylated targets for eight frequent tumor types (lung, breast, colorectal, prostate, pancreatic, head and neck, liver, and esophageal cancer). Three targets were validated using ddPCR in 103 tumor and 109 normal adjacent fresh frozen samples. Two distinct ddPCR assays were successfully developed. Output data from both assays is combined to obtain a read-out from the three targets together. Our overall ddPCR assay has a cross-validated area under the curve (cvAUC) of 0.948. Performance between distinct cancer types varies, with sensitivities ranging from 53.8% to 100% and specificities ranging from 80% to 100%. Compared to previously published single-target parameters, we show that combining targets can drastically increase sensitivity and specificity, while lowering DNA input. In conclusion, we are the first to report a multi-cancer methylation ddPCR assay, which allows for highly accurate tumor predictions.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142140469","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":"A method to quantitatively characterize the formation and dissociation of tumor cell clusters using light transmission aggregometry.","authors":"Regina Komal Kottana, Brian Schnoor, Anne-Laure Papa","doi":"10.1002/1878-0261.13723","DOIUrl":"https://doi.org/10.1002/1878-0261.13723","url":null,"abstract":"<p><p>In this paper, we have modified the workflow of the traditional light transmission aggregometry (LTA) protocol to characterize tumor cell clusters in vitro in a quantifiable and multifaceted manner. Circulating tumor cell (CTC) clusters have high metastatic potential compared to single tumor cells traveling in the bloodstream. Thus, engineering new therapeutic strategies that specifically target this CTC population is essential. To accomplish this, quantifiable methods to characterize their therapeutic effect on tumor cell clusters is a prerequisite. The method presented here enables the user to precisely quantify the dissociation of cancer cell clusters in the presence of clinically relevant fibrinolytic agents, such as alteplase and tenecteplase. The efficacy of the fibrinolytic agents can be quantified using this in vitro assay, prior to conducting preclinical studies. Here, we have obtained the fibrinolytic activity data in terms of lag time to the initiation of tumor cell dissociation, time to 25% dissociation, and trend of dissociation over time. To validate the assay, cell counts and phase-contrast microscopy images were recorded over time. Further, we explored an LTA-assisted preparation of platelet-tumor-cell clusters of calibrated size for potential downstream testing/applications. To assess whether the assay is applicable to characterize the dissociation of cancer cell clusters in the presence of platelets, we added low (50 000 platelets·μL^-1), normal (200 000 platelets·μL^-1) and high (450 000 platelets·μL^-1) concentrations of platelets to the tumor cell clusters. In addition to dissociation parameters, microcopy images were recorded over time to validate the assay and enabled the enumeration of clusters and single cells. The correlative light electron microscopy (CLEM) technique was utilized to visualize the morphology and composition of platelet-tumor cell clusters.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142133214","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 one-carbon metabolic enzyme MTHFD2 promotes resection and homologous recombination after ionizing radiation.","authors":"Petra Marttila, Nadilly Bonagas, Christina Chalkiadaki, Hannah Stigsdotter, Korbinian Schelzig, Jianyu Shen, Crystal M Farhat, Amber Hondema, Julian Albers, Elisée Wiita, Azita Rasti, Ulrika Warpman Berglund, Ana Slipicevic, Oliver Mortusewicz, Thomas Helleday","doi":"10.1002/1878-0261.13645","DOIUrl":"10.1002/1878-0261.13645","url":null,"abstract":"<p><p>The one-carbon metabolism enzyme bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase 2 (MTHFD2) is among the most overexpressed proteins across tumors and is widely recognized as a promising anticancer target. While MTHFD2 is mainly described as a mitochondrial protein, a new nuclear function is emerging. Here, we observe that nuclear MTHFD2 protein levels and association with chromatin increase following ionizing radiation (IR) in an ataxia telangiectasia mutated (ATM)- and DNA-dependent protein kinase (DNA-PK)-dependent manner. Furthermore, repair of IR-induced DNA double-strand breaks (DSBs) is delayed upon MTHFD2 knockdown, suggesting a role for MTHFD2 in DSB repair. In support of this, we observe impaired recruitment of replication protein A (RPA), reduced resection, decreased IR-induced DNA repair protein RAD51 homolog 1 (RAD51) levels and impaired homologous recombination (HR) activity in MTHFD2-depleted cells following IR. In conclusion, we identify a key role for MTHFD2 in HR repair and describe an interdependency between MTHFD2 and HR proficiency that could potentially be exploited for cancer therapy.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"2179-2195"},"PeriodicalIF":6.6,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11467796/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140293990","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 metabolic reprogramming to overcome drug resistance in advanced bladder cancer: insights from gemcitabine- and cisplatin-resistant models.","authors":"Ichiro Kawahara, Hirofumi Yoshino, Wataru Fukumoto, Junya Arima, Saeki Saito, Gang Li, Ikumi Fukuda, Akihiko Mitsuke, Takashi Sakaguchi, Satoru Inoguchi, Ryosuke Matsushita, Masayuki Nakagawa, Shuichi Tatarano, Yasutoshi Yamada, Hideki Enokida","doi":"10.1002/1878-0261.13684","DOIUrl":"10.1002/1878-0261.13684","url":null,"abstract":"<p><p>Gemcitabine plus cisplatin (GC) combination chemotherapy is the primary treatment for advanced bladder cancer (BC) with unresectable or metastatic disease. However, most cases develop resistance to this therapy. We investigated whether drug resistance could be targeted through metabolic reprogramming therapies. Metabolomics analyses in our lab's gemcitabine- and cisplatin-resistant cell lines revealed increased phosphoglycerate dehydrogenase (PHGDH) expression in gemcitabine-resistant cells compared with parental cells. Isocitrate dehydrogenase 2 (IDH2) gain of function stabilized hypoxia-inducible factor1α (HIF1α) expression, stimulating aerobic glycolysis. In gemcitabine-resistant cells, elevated fumaric acid suppressed prolyl hydroxylase domain-containing protein 2/Egl nine homolog 1 (PHD2) and stabilized HIF1α expression. PHGDH downregulation or inhibition in gemcitabine-resistant BC cells inhibited their proliferation, migration, and invasion. Cisplatin-resistant cells showed elevated fatty acid metabolism, upregulating fatty acid synthase (FASN) downstream of tyrosine kinase. Using the fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor erdafitinib, we inhibited malonyl-CoA production, which is crucial for fatty acid synthesis, and thereby suppressed upregulated HIF1α expression. Combination treatment with NCT503 and erdafitinib synergistically suppressed tumor cell proliferation and induced apoptosis in vitro and in vivo. Understanding these mechanisms could enable innovative BC therapeutic strategies to be developed.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"2196-2211"},"PeriodicalIF":6.6,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11467791/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141317804","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}