Molecular Cancer Therapeutics最新文献

{"title":"Targeting PDHK1 by DCA to Restore NK Cell Function in Hepatocellular Carcinoma.","authors":"Xinyi Yang, Yuanyuan Liu, Peng Wang, Min Li, Tong Xiang, Songzuo Xie, Minxing Li, Yan Wang, Desheng Weng, Jingjing Zhao","doi":"10.1158/1535-7163.MCT-24-0222","DOIUrl":"10.1158/1535-7163.MCT-24-0222","url":null,"abstract":"<p><p>Pyruvate dehydrogenase complex is a crucial enzyme involved in the oxidation of glucose. It is regulated by pyruvate dehydrogenase kinase (PDHK) and pyruvate dehydrogenase phosphatase. Studies have demonstrated that PDHK1, a key enzyme in glucose metabolism, behaves like oncogenes. It is highly expressed in tumors and is associated with poor patient prognosis. However, there is limited research on how PDHK1 affects immune cell function. We have established a model of NK cell exhaustion to investigate the impact of dichloroacetate (DCA) on NK cell function. The production of granzyme B, IFNγ, TNFα, and CD107a by NK cells was explored by flow cytometry. The real-time live-cell imaging system was used to monitor the ability of NK cells against tumor cells. The Seahorse analyzer was utilized to measure the oxygen consumption rate and extracellular acidification rate of NK cells. A mouse model was used to investigate the potential of combining DCA with adjuvant NK cell infusion. Our study demonstrated that the hepatocellular carcinoma microenvironment mediated NK cellular exhaustion and high expression of PDHK1 and reduced cytokine secretion. We discovered that the PDHK1 inhibitor DCA enhances the activity and function of exhausted NK cells infiltrating the tumor microenvironment. Furthermore, in a s.c. hepatocellular carcinoma mouse model, DCA combined with NK cell treatment resulted in retarding cancer progression. This study indicates the potential of DCA in rescuing NK cell exhaustion and eliciting antitumor immunity.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1731-1742"},"PeriodicalIF":5.3,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142004820","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 Synthetic Lethal Relationship between FOCAD and TUT7 Represents a Potential Therapeutic Opportunity for TUT4/7 Small-Molecule Inhibitors in Cancer.","authors":"Robinson Triboulet, Khikmet Sadykov, Darren M Harvey, David M Wilson, Michael J Steinbaugh, Christopher B Mayo, Dillon Hawley, Andrew Madanjian, Corey Fyfe, Christina Bracken, Izarys Rivera-Rivera, Anna Ericsson, Andrew R Snyder, Sarah K Knutson, Ross L Stein, Veronica Gibaja, Shomir Ghosh, Robert M Campbell","doi":"10.1158/1535-7163.MCT-24-0176","DOIUrl":"10.1158/1535-7163.MCT-24-0176","url":null,"abstract":"<p><p>Targeting synthetic lethal interactions among genes has emerged as a promising strategy for cancer therapy. This study explores the intricate interplay among terminal uridylyltransferase 4 (TUT4) and terminal uridylyltransferase 7 (TUT7), the 3'-5' exoribonuclease DIS3L2, and the superkiller (SKI) complex-interacting factor focadhesin (FOCAD) in the context of cancer vulnerability. Using CRISPR and public functional genomics data, we show impairment of cell proliferation upon knockout of TUT7 or DIS3L2, but not TUT4, on cancer cells with FOCAD loss. Moreover, we report the characterization of the first potent and selective TUT4/7 inhibitors that substantially reduce uridylation and demonstrate in vitro and in vivo antiproliferative activity specifically in FOCAD-deleted cancer. FOCAD deficiency posttranscriptionally disrupts the stability of the SKI complex, whose role is to safeguard cells against aberrant RNA. Reintroduction of FOCAD restores the SKI complex and makes these cells less sensitive to TUT4/7 inhibitors, indicating that TUT7 dependency is driven by FOCAD loss. We propose a model in which, in the absence of FOCAD, TUT7 and DIS3L2 function as a salvage mechanism that degrades aberrant RNA, and genetic or pharmacologic inhibition of this pathway leads to cell death. Our findings underscore the significance of FOCAD loss as a genetic driver of TUT7 vulnerability and provide insights into the potential utility of TUT4/7 inhibitors for cancer treatment.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1779-1788"},"PeriodicalIF":5.3,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142133245","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":"TR-107, an Agonist of Caseinolytic Peptidase Proteolytic Subunit, Disrupts Mitochondrial Metabolism and Inhibits the Growth of Human Colorectal Cancer Cells.","authors":"Michael Giarrizzo, Joseph F LaComb, Hetvi R Patel, Rohan G Reddy, John D Haley, Lee M Graves, Edwin J Iwanowicz, Agnieszka B Bialkowska","doi":"10.1158/1535-7163.MCT-24-0170","DOIUrl":"10.1158/1535-7163.MCT-24-0170","url":null,"abstract":"<p><p>Oxidative phosphorylation is an essential metabolic process for cancer proliferation and therapy resistance. The ClpXP complex maintains mitochondrial proteostasis by degrading misfolded proteins. Madera Therapeutics has developed a class of highly potent and selective small-molecule activators (TR compounds) of the ClpXP component caseinolytic peptidase proteolytic subunit (ClpP). This approach to cancer therapy eliminates substrate recognition and activates nonspecific protease function within mitochondria, which has shown encouraging preclinical efficacy in multiple malignancies. The class-leading compound TR-107 has demonstrated significantly improved potency in ClpP affinity and activation and enhanced pharmacokinetic properties over the multitargeting clinical agent ONC201. In this study, we investigate the in vitro efficacy of TR-107 against human colorectal cancer cells. TR-107 inhibited colorectal cancer cell proliferation in a dose- and time-dependent manner and induced cell cycle arrest at low nanomolar concentrations. Mechanistically, TR-107 downregulated the expression of proteins involved in the mitochondrial unfolded protein response and mitochondrial DNA transcription and translation. TR-107 attenuated oxygen consumption rate and glycolytic compensation, confirming inactivation of oxidative phosphorylation and a reduction in total cellular respiration. Multiomics analysis of treated cells indicated a downregulation of respiratory chain complex subunits and an upregulation of mitophagy and ferroptosis pathways. Further evaluation of ferroptosis revealed a depletion of antioxidant and iron toxicity defenses that could potentiate sensitivity to combinatory chemotherapeutics. Together, this study provides evidence and insight into the subcellular mechanisms employed by colorectal cancer cells in response to potent ClpP agonism. Our findings demonstrate a productive approach to disrupting mitochondrial metabolism, supporting the translational potential of TR-107.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1761-1778"},"PeriodicalIF":5.3,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11614700/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142133246","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":"Advanced Human Papillomavirus-Negative Head and Neck Squamous Cell Carcinoma: Unmet Need and Emerging Therapies.","authors":"Robin Park, Christine H Chung","doi":"10.1158/1535-7163.MCT-24-0281","DOIUrl":"10.1158/1535-7163.MCT-24-0281","url":null,"abstract":"<p><p>Despite notable progress in the treatment of advanced head and neck squamous cell carcinoma (HNSCC), survival remains poor in patients with recurrent and/or metastatic (R/M) human papillomavirus (HPV)-negative HNSCC. Worse outcomes in patients who are HPV-negative may be partly related to loss of cell-cycle regulators and tumor suppressors as well as a noninflamed and hypoxic tumor microenvironment, both of which contribute to treatment resistance and disease progression. Anti-programmed cell death protein 1-based regimens as current standard-of-care treatment for R/M HNSCC are associated with durable responses in a limited number of patients. The anti-EGFR mAb, cetuximab, has antitumor activity in this treatment setting, but responses are short-lived and inevitably curtailed due to treatment resistance. Crosstalk between the EGFR and hepatocyte growth factor-dependent mesenchymal-epithelial transition (c-MET) receptor tyrosine kinase pathway is a known mechanism of resistance to cetuximab. Dual targeting of EGFR and c-MET pathways may overcome resistance to cetuximab in patients with HPV-negative HNSCC. Here, we review clinical data of treatments evaluated in patients with R/M HPV-negative HNSCC and highlight the potential role of combining hepatocyte growth factor/c-MET and EGFR pathway inhibitors to overcome cetuximab resistance in this population.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1717-1730"},"PeriodicalIF":5.3,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11612620/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142291432","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":"Response to systemic therapies in patient-derived cell lines from primary and recurrent adult granulosa cell tumors.","authors":"Geertruid J Brink, Nizar Hami, Sander Mertens, Hans W Nijman, Luc Rcw van Lonkhuijzen, Eva Maria Roes, Christine A R Lok, Cornelis D de Kroon, Jurgen Mj Piek, Ward Hofhuis, Hugo J G Snippert, Jolijn Willemijntje Groeneweg, Petronella O Witteveen, Ronald P Zweemer","doi":"10.1158/1535-7163.MCT-24-0223","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0223","url":null,"abstract":"<p><p>In patients with the rare adult-type granulosa cell tumors (aGCT), surgery is the primary treatment for both primary and recurrent disease. In cases of inoperable disease, systematic therapy is administered, but variable response rates and drug resistance complicate predicting the most effective therapy. Drug screen testing on patient-derived cell lines may offer a solution. In a national prospective study on aGCT, fresh tissue was cultured into 2D cell lines, testing 27 clinically and experimental drugs. Dose-response curves and synergy were calculated using GraphPad Prism and Compusyn software. We established 34 patient-derived cell lines from tissue of 20 adult granulosa cell tumor patients. Of these, seven patients had a primary diagnosis of adult granulosa cell tumor and 13 patients had recurrent disease. In eight patients multiple tumor locations were cultured. On each cell line 10 monotherapies and 17 combinations of drugs were tested. Carboplatin/gemcitabine showed efficacy and synergy in almost all patient-derived cell lines. Synergy could not be detected in the regular carboplatin/paclitaxel and carboplatin/etoposide combinations. Experimental combinations alpelisib/fulvestrant and alpelisib/gemcitabine showed efficacy of more than 75%. Drug screens on patient-derived tumor cell lines reflects the reality of the variable response of systemic therapy in aGCT patients. In future research, this technique may be used to personalize the systemic treatment of aGCT patients in a clinical study. The good response to carboplatin/gemcitabine in our patient-derived cell lines can then be confirmed in a clinical setting.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142730738","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 CDK7 enhances the antitumor efficacy of enzalutamide in androgen receptor-positive triple-negative breast cancer by inhibiting c-MYC-mediated tumorigenesis.","authors":"Xuemei Xie, Maroua Manai, Dileep R Rampa, Jon A Fuson, Elizabeth S Nakasone, Troy Pearson, Bharat S Kuntal, Debu Tripathy, Naoto T Ueno, Jangsoon Lee","doi":"10.1158/1535-7163.MCT-23-0386","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-23-0386","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer. Among TNBC subtypes, the luminal androgen receptor (LAR) subtype expresses high levels of androgen receptor (AR) and generally responds poorly to neoadjuvant chemotherapy. AR has been reported as a promising therapeutic target for the LAR TNBC subtype. Here, we evaluated the preclinical antitumor efficacy of enzalutamide, an AR inhibitor, in TNBC. Enzalutamide had moderate anti-proliferation activity against AR-positive (AR+) TNBC cells (IC50 > 15 µM). To enhance its antitumor efficacy, we performed high-throughput kinome siRNA screening and identified the cell cycle pathway as a potential target. Inhibition of cell cycle progression using the CDK7 inhibitor KRLS-017 showed a synergistic anti-proliferation effect with enzalutamide in AR+ LAR MDA-MB-453 and SUM185 TNBC cells. Downstream target analysis revealed that enzalutamide and KRLS-017 combination dramatically reduced c-MYC expression at both mRNA and protein levels. c-MYC knockdown significantly suppressed growth of MDA-MB-453 and SUM185 cells to a degree comparable to that of enzalutamide and KRLS-017 combination treatment, whereas c-MYC overexpression reversed the synergistic effect. An enhancement in inhibition of tumor growth and suppression of c-MYC expression was further confirmed when enzalutamide combined with KRLS-017 in an MDA-MB-453 mouse model. Our study suggests that KRLS-017 enhances the antitumor efficacy of enzalutamide by inhibiting c-MYC-mediated tumorigenesis and presents a potential new approach for treating AR+ LAR TNBC.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142716593","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":"Novel Amanitin-based Antibody Drug Conjugates (ATAC®) targeting TROP2 for the treatment of Pancreatic Cancer.","authors":"Eleni Papacharisi, Alexandra Braun, Marija Vranic, Andreas M Pahl, Torsten Hechler","doi":"10.1158/1535-7163.MCT-24-0266","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0266","url":null,"abstract":"<p><p>Trophoblast cell surface antigen 2 (TROP2) exhibits aberrant expression in pancreatic cancer, correlating with metastasis, advanced tumor stage and poor prognosis of pancreatic ductal adenocarcinoma (PDAC) patients. TROP2 has been recognized as a promising therapeutic target for antibody drug conjugates (ADCs), as evidenced by the approval of the anti-TROP2 ADC Trodelvy® for the treatment of triple negative breast cancer. In this study we report the generation of novel second-generation amanitin based ADCs (ATAC®s) targeting TROP2, comprising the humanized RS7 antibody of Trodelvy® (hRS7) and the highly potent payload amanitin. The specific in vitro binding, efficient antigen internalization, and high cytotoxicity of hRS7 ATAC®s with half maximal effective concentration (EC50) values in the picomolar range in TROP2-expressing cells constituted the foundation for preclinical in vivo evaluation. The hRS7 ATAC®s demonstrated a significant reduction in tumor growth in vivo in subcutaneous xenograft mouse models of pancreatic cancer and triple negative breast cancer at well-tolerated doses. The antitumor efficacy correlated with the level of TROP2 expression on the tumors and the in vivo tumor uptake of the ATAC®s. The long half-life of 9.7-10.7 days of hRS7 ATAC®s without premature payload release in serum supported a high therapeutic index. Notably, the efficacy of the hRS7 ATAC®s was superior to that of Trodelvy® with complete tumor eradication in both, refractory pancreatic and triple negative breast cancer xenograft models. In summary, hRS7 ATAC®s represent a highly effective and well-tolerated targeted therapy, and our data support their development for pancreatic cancer and other TROP2-expressing tumors.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142676379","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":"Trastuzumab-MMAU Antibody-Auristatin Conjugates: Valine-Glucoserine Linker with Stabilized Maleimide Conjugation Improves In Vivo Efficacy and Tolerability.","authors":"Shalom D Goldberg, Tero Satomaa, Olulanu Aina, Olli Aitio, Krista Burke, Vadim Dudkin, Brian Geist, Onyi Irrechukwu, Anna-Liisa Hänninen, Annamari Heiskanen, Jari Helin, Jukka O Hiltunen, Jacqueline Kinyamu-Akunda, Donna M Klein, Neeraj Kohli, Titta Kotiranta, Tuula Lähteenmäki, Ritva Niemelä, Virve Pitkänen, Henna Pynnönen, William Rittase, Kristen Wiley, Junguo Zhou, Juhani Saarinen","doi":"10.1158/1535-7163.MCT-23-0591","DOIUrl":"10.1158/1535-7163.MCT-23-0591","url":null,"abstract":"<p><p>Antibody-drug conjugates (ADC) have shown impressive clinical activity with approval of many agents in hematologic and solid tumors. However, challenges remain with both efficacy and safety of ADCs. This study describes novel trastuzumab-auristatin conjugates with the hydrophilic monomethylauristatin E (MMAE) prodrug MMAU, and optimization of a glycopeptide linker leading to a wider therapeutic window. Trastuzumab was conjugated with auristatin payloads via a series of linkers using a stabilized maleimide handle. The ADCs were characterized in vitro and their relative in vivo antitumor efficacies were assessed in HER2+ xenograft models. Relative linker stabilities and the mechanism of linker cleavage were studied using in vitro assays. Toxicity and toxicokinetics of the best performing ADC were evaluated in cynomolgus monkey (cyno). The trastuzumab-MMAU ADC with stabilized glycopeptide linker showed maleimide stabilization and higher resistance to cleavage by serum and lysosomal enzymes compared with a valine-citrulline conjugated trastuzumab ADC (trastuzumab-vc-MMAE). A single dose of 1 or 2 mg/kg of trastuzumab-MMAU at drug-to-antibody ratios (DAR) of eight and four respectively resulted in xenograft tumor growth inhibition, with superior efficacy to trastuzumab-vc-MMAE. Trastuzumab-MMAUDAR4 was tolerated at doses up to 12 mg/kg in cyno, which represents 2- to 4-fold higher dose than that observed with vedotin ADCs, and had increased terminal half-life and exposure. The optimized trastuzumab-MMAU ADC showed potent antitumor activity and was well tolerated with excellent pharmacokinetics in nonhuman primates, leading to a superior preclinical therapeutic window. The data support potential utility of trastuzumab-MMAU for treatment of HER2+ tumors.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1530-1543"},"PeriodicalIF":5.3,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139697853","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 Microenvironment Reprogramming Improves Nanomedicine-Based Chemo-Immunotherapy in Sarcomas.","authors":"Antonia Charalambous, Fotios Mpekris, Myrofora Panagi, Chrysovalantis Voutouri, Christina Michael, Alberto A Gabizon, Triantafyllos Stylianopoulos","doi":"10.1158/1535-7163.MCT-23-0772","DOIUrl":"10.1158/1535-7163.MCT-23-0772","url":null,"abstract":"<p><p>Sarcomas are a heterogeneous group of rare cancers that originate in soft tissues or bones. Their complexity and tendency for metastases make treatment challenging, highlighting the need for new therapeutic approaches to improve patient survival. The difficulties in treating these cancers primarily stem from abnormalities within the tumor microenvironment (TME), which leads to reduced blood flow and oxygen levels in tumors. Consequently, this hampers the effective delivery of drugs to tumors and diminishes treatment efficacy despite higher toxic doses of chemotherapy. In this study, we tested the mechanotherapeutic ketotifen combined with either pegylated liposomal doxorubicin (PLD) or pegylated liposomal coencapsulated alendronate-doxorubicin (PLAD) plus anti-programmed cell death protein 1 antibody in mouse models of fibrosarcoma and osteosarcoma. We found that ketotifen successfully reprogrammed the TME by reducing tumor stiffness and increasing perfusion, proven by changes measured by shear-wave elastography and contrast-enhanced ultrasound, respectively, and enhanced the therapeutic efficacy of our nanomedicine-based chemo-immunotherapy protocols. Furthermore, we observed a trend toward improved antitumor responses when nano-chemotherapy is given alongside anti-programmed cell death protein 1 and when the immunomodulator alendronate was present in the treatment. We next investigated the mechanisms of action of this combination. Ketotifen combined with nanomedicine-based chemo-immunotherapy increased T-cell infiltration, specifically cytotoxic CD8+ T cells and CD4+ T helper cells, and decreased the number of regulatory T cells. In addition, the combination also altered the polarization of tumor-associated macrophages, favoring the M1 immune-supportive phenotype over the M2 immunosuppressive phenotype. Collectively, our findings provide evidence that ketotifen-induced TME reprogramming can improve the efficacy of nanomedicine-based chemo-immunotherapy in sarcomas.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1555-1567"},"PeriodicalIF":5.3,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141469558","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":"YAP1 Suppression by ZDHHC7 Is Associated with Ferroptosis Resistance and Poor Prognosis in Ovarian Clear Cell Carcinoma.","authors":"Yoko Furutake, Ken Yamaguchi, Koji Yamanoi, Sachiko Kitamura, Shiro Takamatsu, Mana Taki, Masayo Ukita, Yuko Hosoe, Ryusuke Murakami, Kaoru Abiko, Akihito Horie, Junzo Hamanishi, Tsukasa Baba, Noriomi Matsumura, Masaki Mandai","doi":"10.1158/1535-7163.MCT-24-0145","DOIUrl":"10.1158/1535-7163.MCT-24-0145","url":null,"abstract":"<p><p>Ovarian clear cell carcinoma (OCCC), which has unique clinical characteristics, arises from benign endometriotic cysts, forming an oxidative stress environment because of excess iron accumulation, and exhibits poor prognosis, particularly in advanced stages owing to resistance to conventional therapeutics. Ferroptosis is an iron-dependent form of programmed cell death induced by lipid peroxidation and controlled by Hippo signaling. We hypothesized that overcoming ferroptosis resistance is an attractive strategy because OCCC acquires oxidative stress resistance during its development and exhibits chemoresistant features indicative of ferroptosis resistance. This study aimed to determine whether OCCC is resistant to ferroptosis and clarify the mechanism underlying resistance. Unlike ovarian high-grade serous carcinoma cells, OCCC cells were exposed to oxidative stress. However, OCCC cells remained unaffected by lipid peroxidation. Cell viability assays revealed that OCCC cells exhibited resistance to the ferroptosis inducer erastin. Moreover, Samroc analysis showed that the Hippo signaling pathway was enriched in OCCC cell lines and clinical samples. Furthermore, patients with low expression of nuclear yes-associated protein 1 (YAP1) exhibited a significantly poor prognosis of OCCC. Moreover, YAP1 activation enhanced ferroptosis in OCCC cell lines. Furthermore, suppression of zinc finger DHHC-type palmitoyltransferase 7 (ZDHHC7) enhanced ferroptosis by activating YAP1 in OCCC cell lines. Mouse xenograft models demonstrated that ZDHHC7 inhibition suppressed tumor growth via YAP1 activation by erastin treatment. In conclusion, YAP1 activation regulated by ZDHHC7 enhanced ferroptosis in OCCC. Thus, overcoming ferroptosis resistance is a potential therapeutic strategy for OCCC.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1652-1665"},"PeriodicalIF":5.3,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141492666","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}