Molecular Cancer Therapeutics最新文献

{"title":"Prognostic Significance of SASP-Related Gene Signature of Radiation Therapy in Head and Neck Squamous Cell Carcinoma.","authors":"Min Kyeong Lee, Seon Rang Woo, Joo Kyung Noh, Soonki Min, Moonkyoo Kong, Young Chan Lee, Seong-Gyu Ko, Young-Gyu Eun","doi":"10.1158/1535-7163.MCT-23-0738","DOIUrl":"10.1158/1535-7163.MCT-23-0738","url":null,"abstract":"<p><p>In this study, we developed and validated the clinical significance of senescence-associated secretory phenotype (SASP)-related gene signature and explored its association with radiation therapy (RT) in patients with head and neck squamous cell carcinoma (HNSCC). First, we searched the three published review literature associated with SASP and selected all 81 genes to develop SASP-related gene signature. Then, 81 SASP-related genes were adapted to gene expression dataset from The Cancer Genome Atlas (TCGA). Patients with HNSCC of TCGA were classified into clusters 1 and 2 via unsupervised clustering according to SASP-related gene signature. Kaplan-Meier plot survival analysis showed that cluster 1 had a poorer prognosis than cluster 2 in 5-year overall survival and recurrence-free survival. Similarly, cluster 1 showed a worse prognosis than cluster 2 in three validation cohorts (E-MTAB-8588, FHCRC, and KHU). Cox proportional hazards regression observed that the SASP-related signature was an independent prognostic factor for patients with HNSCC. We also established a nomogram using a relevant clinical parameter and a risk score. Time-dependent receiver operating characteristic analysis was carried out to assess the accuracy of the prognostic risk model and nomogram. Senescence SASP-related gene signature was associated with the response to RT. Therefore, subsequent, in vitro experiments further validated the association between SASP-related gene signature and RT in HNSCC. In conclusion, we developed a SASP-related gene signature, which could predict survival of patients with HNSCC, and this gene signature provides new clinical evidence for the accurate diagnosis and targeted RT of HNSCC.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141498502","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":"Radiation and Chemo-Sensitizing Effects of DNA-PK Inhibitors Are Proportional in Tumors and Normal Tissues.","authors":"Jennifer H E Baker, Alastair H Kyle, Nannan A Liu, Taixiang Wang, Xinhe Liu, Sevin Teymori, Judit P Banáth, Andrew I Minchinton","doi":"10.1158/1535-7163.MCT-23-0681","DOIUrl":"10.1158/1535-7163.MCT-23-0681","url":null,"abstract":"<p><p>Inhibitors of DNA-dependent protein kinase (PRKDC; DNA-PK) sensitize cancers to radiotherapy and DNA-damaging chemotherapies, with candidates in clinical trials. However, the degree to which DNA-PK inhibitors also sensitize normal tissues remains poorly characterized. In this study, we compare tumor growth control and normal tissue sensitization following DNA-PK inhibitors in combination with radiation and etoposide. FaDu tumor xenografts implanted in mice were treated with 10 to 15 Gy irradiation ± 3 to 100 mg/kg AZD7648. A dose-dependent increase in time to tumor volume doubling following AZD7648 was proportional to an increase in toxicity scores of the overlying skin. Similar effects were seen in the intestinal jejunum, tongue, and FaDu tumor xenografts of mice assessed for proliferation rates at 3.5 days after treatment with etoposide or 5 Gy whole body irradiation ± DNA-PK inhibitors AZD7648 or peposertib (M3814). Additional organs were examined for sensitivity to DNA-PK inhibitor activity in ATM-deficient mice, where DNA-PK activity is indicated by surrogate marker γH2AX. Inhibition was observed in the heart, brain, pancreas, thymus, tongue, and salivary glands of ATM-deficient mice treated with the DNA-PK inhibitors relative to radiation alone. Similar reductions are also seen in ATM-deficient FaDu tumor xenografts where both pDNA-PK and γH2AX staining could be performed. DNA-PK inhibitor-mediated sensitization to radiation and DNA-damaging chemotherapy are not only limited to tumor tissues, but also extends to normal tissues sustaining DNA damage. These data are useful for interpretation of the sensitizing effects of DNA damage repair inhibitors, where a therapeutic index showing greater cell-killing effects on cancer cells is crucial for optimal clinical translation.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141087791","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":"Immunoproteasome activation expands the MHC class I immunopeptidome, unmasks neoantigens and enhances T-cell antimyeloma activity.","authors":"Priyanka S Rana, James J Ignatz-Hoover, Chunna Guo, Amber L Mosley, Ehsan Malek, Yuriy Fedorov, Drew J Adams, James J Driscoll","doi":"10.1158/1535-7163.MCT-23-0931","DOIUrl":"10.1158/1535-7163.MCT-23-0931","url":null,"abstract":"<p><p>Proteasomes generate antigenic peptides that are presented on the tumor surface to cytotoxic T-lymphocytes (CTLs). Immunoproteasomes are highly-specialized proteasome variants that are expressed at higher levels in antigen-presenting cells and contain replacements of the three constitutive proteasome catalytic subunits to generate peptides with a hydrophobic C-terminus that fit within the groove of MHC class I (MHC-I) molecules. A hallmark of cancer is the ability to evade immunosurveillance by disrupting the antigen presentation machinery and downregulating MHC-I antigen presentation. High-throughput screening was performed to identify Compound A, a novel molecule that selectively increased immunoproteasome activity and expanded the number and diversity of MHC-I-bound peptides presented on multiple myeloma (MM) cells. Compound A increased the presentation of individual MHC-I-bound peptides >100-fold and unmasked tumor-specific neoantigens on myeloma cells. Global proteomic integral stability assays determined that Compound A binds the proteasome structural subunit PSMA1 and promotes association of the proteasome activator PA28α/β (PSME1/PSME2) with immunoproteasomes. CRISPR/Cas9 silencing of PSMA1, PSME1, or PSME2 as well as treatment with immunoproteasome-specific suicide inhibitors abolished the effects of Compound A on antigen presentation. Treatment of MM cell lines and patient bone marrow-derived CD138+ cells with Compound A increased the antimyeloma activity of allogenic and autologous T-cells. Compound A was well-tolerated in vivo and co-treatment with allogeneic T-cells reduced the growth of myeloma xenotransplants in NSG mice. Taken together, our results demonstrate the paradigm-shifting impact of immunoproteasome activators to diversify the antigenic landscape, expand the immunopeptidome, potentiate T-cell-directed therapy, and reveal actionable neoantigens for personalized T-cell immunotherapy.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142109603","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":"Fatty acid derivatization and cyclization of the immunomodulatory peptide RP-182 targeting CD206high macrophages improves anti-tumor activity.","authors":"Sitanshu S Singh, Raul Calvo, Anju Kumari, Rushikesh V Sable, Yuhong Fang, Dingyin Tao, Xin Hu, Sarah Gray Castle, Saifun Nahar, Dandan Li, Emily Major, Tino W Sanchez, Rintaro Kato, Xin Xu, Jian Zhou, Liang Liu, Christopher A LeClair, Anton Simeonov, Bolormaa Baljinnyam, Mark J Henderson, Juan Marugan, Udo Rudloff","doi":"10.1158/1535-7163.MCT-23-0790","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-23-0790","url":null,"abstract":"<p><p>As tumor-associated macrophages (TAMs) exercise a plethora of pro-tumor and immune evasive functions, novel strategies targeting TAMs to inhibit tumor progression have emerged within the current arena of cancer immunotherapy. Activation of the mannose receptor 1 (Mrc1; CD206) is a recent approach that recognizes immune suppressive CD206high M2-like TAMs as a drug target. Ligation of CD206 both induces reprogramming of CD206high TAMs towards a pro-inflammatory phenotype and selectively triggers apoptosis in these cells. CD206-activating therapeutics are currently limited to the linear, 10mer peptide RP-182, 1, which is not a drug candidate. Here we sought to identify a better suitable candidate for future clinical development by synthesizing and evaluating a series of RP-182 analogues. Surprisingly, fatty acid derivative 1a (RP-182-PEG3-K(palmitic acid)) not only showed improved stability but also increased affinity to the CD206 receptor through enhanced interaction with a hydrophobic binding motif of CD206. Peptide 1a showed superior in vitro activity in cell-based assays of macrophage activation which was restricted to CD206high M2-polarized macrophages. Improvement of responses was disproportionally skewed towards improved induction of phagocytosis including cancer cell phagocytosis. 1a reprogrammed the immune landscape in genetically engineered murine KPC pancreatic tumors towards increased innate immune surveillance and improved tumor control, and effectively suppressed tumor growth of murine B16 melanoma allografts.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142109602","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":"SC134-TCB targeting fucosyl-GM1, a T cell engaging antibody with potent anti-tumour activity in preclinical small-cell lung cancer models.","authors":"Foram Dave, Poonam Vaghela, Bryony Heath, Zuzana Dunster, Elena Dubinina, Dhruma Thakker, Katie Mann, Joe Chadwick, Gaelle Cane, Bubacarr G Kaira, Omar J Mohammed, Ruhul Choudhury, Samantha Paston, Tina Parsons, Mireille Vankemmelbeke, Lindy Durrant","doi":"10.1158/1535-7163.MCT-24-0187","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0187","url":null,"abstract":"<p><p>Small-cell lung cancer (SCLC) is an aggressive disease with limited treatment options. Fucosyl-GM1 (FucGM1) is a glycolipid overexpressed in the majority of SCLC tumours, but virtually absent from normal healthy tissues. Here, we validate a FucGM1-targeting T cell redirecting bispecific antibody (TCB) for the treatment of SCLC. Over 80% of SCLC patient-derived xenograft (PDX) tissues expressed FucGM1, whilst only three normal human tissues: pituitary, thymus and skin expressed low and focal FucGM1. A FucGM1-targeting TCB (SC134-TCB), based on the Fc-silenced humanised h134 antibody exhibited nanomolar FucGM1 glycolipid and SCLC cell surface binding. SC134-TCB showed potent ex vivo killing of SCLC cell lines with donor-dependent EC50 ranging from 7.2 pmol/L up to 211.0 pmol/L, effectively activating T cells, with picomolar efficiency, coinciding with target-dependent cytokine production such as interferon gamma, interleukin-2 and tumour necrosis factor alpha and robust proliferation of both CD4 and CD8 T cells. The ex vivo SC134-TCB tumour controlling activity translated into an effective in vivo anti-DMS79 tumour therapy, resulting in 100% tumour-free survival in a human PBMC admixed setting and 40% overall survival (55% tumour growth inhibition) with systemically administered human PBMC. Combination treatment with Atezolizumab further enhanced survival and tumour growth inhibition (up to 73%). A ten-fold SC134-TCB dose reduction maintained the strong in vivo anti-tumour impact, translating into 70% overall survival (P<0.0001). Whole blood incubation with SC134-TCB, as well as healthy human primary cells analysis, revealed no target-independent cytokine production. SC134-TCB presents an attractive candidate to deliver an effective immunotherapy treatment option for SCLC patients.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142056057","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":"Preclinical Characterization of ARX517, a Site-specific Stable PSMA-Targeted Antibody Drug Conjugate for Treatment of Metastatic Castration-Resistant Prostate Cancer.","authors":"Lillian K Skidmore, David Mills, Ji Young Kim, Nick A Knudsen, Jay D Nelson, Manoj Pal, Jianing Wang, Kedar Gc, Michael J Gray, Wisam Barkho, Prathap Nagaraja Shastri, Mysore P Ramprasad, Feng Tian, Daniel O'Connor, Ying J Buechler, Shawn Shao-Hui Zhang","doi":"10.1158/1535-7163.MCT-23-0927","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-23-0927","url":null,"abstract":"<p><p>Metastatic castration-resistant prostate cancer (mCRPC) is an advanced disease in which patients ultimately fail standard of care androgen-deprivation therapies and exhibit poor survival rates. The prostate-specific membrane antigen (PSMA) has been validated as a mCRPC tumor antigen with over-expression in tumors and low expression in healthy tissues. Using our proprietary technology for incorporating synthetic amino acids (SAAs) into proteins at selected sites, we have developed ARX517, an antibody drug conjugate (ADC) which is composed of a humanized anti-PSMA antibody site-specifically conjugated to a tubulin inhibitor at a drug-to-antibody ratio of 2. After binding PSMA, ARX517 is internalized and catabolized, leading to cytotoxic payload delivery and apoptosis. To minimize premature payload release and maximize delivery to tumor cells, ARX517 employs a non-cleavable PEG linker and stable oxime conjugation enabled via SAA protein incorporation to ensure its overall stability. In vitro studies demonstrate that ARX517 selectively induces cytotoxicity of PSMA-expressing tumor cell lines. ARX517 exhibited a long terminal half-life and high serum exposure in mice, and dose-dependent anti-tumor activity in both enzalutamide-sensitive and -resistant CDX and PDX prostate cancer models. Repeat dose toxicokinetic studies in non-human primates demonstrated ARX517 was tolerated at exposures well above therapeutic exposures in mouse pharmacology studies, indicating a wide therapeutic index. In summary, ARX517 inhibited tumor growth in diverse mCRPC models, demonstrated a tolerable safety profile in monkeys, and had a wide therapeutic index based on preclinical exposure data. Based on the encouraging preclinical data, ARX517 is currently being evaluated in a Phase 1 clinical trial ([NCT04662580]).</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142036417","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":"Dual A2A/ A2B adenosine receptor antagonist M1069 counteracts immuno-suppressive mechanisms of adenosine and reduces tumor growth in vivo.","authors":"Kai Schiemann, Natalya Belousova, Armine Matevossian, Kalyan C Nallaparaju, Giorgio Kradjian, Meghana Pandya, Zhouxiang Chen, Esengul Aral, Eva-Maria Krauel, Elissaveta Petrova, Carsten Boesler, Thomas Kitzing, Marc Lecomte, Christian Wagner, Anne Laure Blayo, Stephan Schann, Bayard Huck, Jacques Moisan, Rinat Zaynagetdinov","doi":"10.1158/1535-7163.MCT-23-0843","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-23-0843","url":null,"abstract":"<p><p>While A2A adenosine receptor (AR) was considered as a major contributor to adenosine-mediated immunosuppression, A2B, having the lowest affinity to adenosine, has also emerged as a potential contributor to tumor promotion. Therefore, in adenosine-rich tumor microenvironment (TME), where A2B could be complementary and/or compensatory to A2A, simultaneous targeting of A2A and A2B ARs can provide higher potential for cancer immunotherapy. We developed M1069 - a highly selective dual antagonist of the A2A and A2B AR. In assays with primary human and murine immune cells, M1069 rescued IL 2 production from T cells (A2A dependent) and inhibited VEGF production by myeloid cells (A2B dependent) in adenosine-high settings. M1069 also demonstrated superior suppression of secretion of pro tumorigenic cytokines CXCL1, CXCL5, and rescue of IL 12 secretion from adenosine differentiated dendritic cells compared to an A2A selective antagonist (A2Ai). In a one-way mixed lymphocyte reaction (MLR) assay, adenosine differentiated human and murine dendritic cells treated with M1069 demonstrated superior T cell stimulatory activity compared to dendritic cells differentiated in presence of A2Ai. In vivo, M1069 decreased tumor growth as a monotherapy and enhanced anti-tumor activity of bintrafusp alfa (BA) or cisplatin in syngeneic adenosinehi/CD73hi 4T1 breast tumor model, but not in the CD73 knockout (KO) 4T1 tumor model or in adenosinelow/CD73low MC38 murine colon carcinoma model. In summary, our dual A2A/A2B AR antagonist M1069 may counteract immune-suppressive mechanisms of high concentrations of adenosine in vitro and in vivo and enhance the anti-tumor activity of other agents, including BA and cisplatin.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142004819","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":"Trametinib potentiates anti-PD-1 efficacy in tumors established from chemotherapy-primed pancreatic cancer cells.","authors":"Thao D Pham, Anastasia E Metropulos, Nida Mubin, Jeffrey H Becker, Dhavan Shah, Christina Spaulding, Mario A Shields, David J Bentrem, Hidayatullah G Munshi","doi":"10.1158/1535-7163.MCT-23-0833","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-23-0833","url":null,"abstract":"<p><p>Despite advances in immune checkpoint inhibitors (ICIs), chemotherapy remains the standard therapy for patients with pancreatic ductal adenocarcinoma (PDAC). As the combinations of chemotherapy, including the FOLFIRINOX (5-fluorouracil (5FU), irinotecan, and oxaliplatin) regimen, and ICIs have failed to demonstrate clinical benefit in patients with metastatic PDAC tumors, there is increasing interest in identifying therapeutic approaches to potentiate ICI efficacy in PDAC patients. In this study, we report that neoadjuvant FOLFRINOX-treated human PDAC tumors exhibit increased MEK/ERK activation. We also show elevated MEK/ERK signaling in ex vivo PDAC slice cultures and cell lines treated with a combination of 5FU (F), irinotecan (I), and oxaliplatin (O) (FIO). In addition, we find that the KPC-FIO cells, established from repeated treatment of mouse PDAC cell lines with 6-8 cycles of FIO, display enhanced ERK phosphorylation and demonstrate increased sensitivity to MEK inhibition in vitro and in vivo. Significantly, the KPC-FIO cells develop tumors with a pro-inflammatory immune profile similar to human PDAC tumors following neoadjuvant FOLFIRINOX treatment. Furthermore, we found that the MEK inhibitor Trametinib enables additional infiltration of highly functional CD8+ T cells into the KPC-FIO tumors and potentiates the efficacy of anti-PD-1 antibody in syngeneic mouse models. Our findings provide a rationale for combining Trametinib and anti-PD-1 antibodies in PDAC patients following neoadjuvant or short-term FOLFIRINOX treatment to achieve effective anti-tumor responses.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142004821","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 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":"https://doi.org/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 and pyruvate dehydrogenase phosphatase. Studies have demonstrated that pyruvate dehydrogenase kinase 1 (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 natural killer (NK) cell exhaustion to investigate the impact of dichloroacetate (DCA) on NK cell function. The production of Granzyme B, IFN-γ, TNF-α, 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 (OCR) and extracellular acidification rate (ECAR) of NK cells. The mouse model was used to investigate the potential of combining DCA with adjuvant NK cell infusion. Our study demonstrated that the hepatocellular carcinoma (HCC) microenvironment mediated NK cellular exhaustion, 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 subcutaneous HCC 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 anti-tumor immunity.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-08-20","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":"Separable cell cycle arrest and immune response elicited through pharmacological CDK4/6 and MEK inhibition in RASmut disease models.","authors":"Jin Wu, Jianxin Wang, Thomas N O'Connor, Stephanie L Tzetzo, Katerina V Gurova, Erik S Knudsen, Agnieszka K Witkiewicz","doi":"10.1158/1535-7163.MCT-24-0369","DOIUrl":"10.1158/1535-7163.MCT-24-0369","url":null,"abstract":"<p><p>The combination of CDK4/6 and MEK inhibition as a therapeutic strategy has shown promise in various cancer models, particularly in those harboring RAS mutations. An initial high-throughput drug screen identified a high synergy between the CDK4/6 inhibitor palbociclib and the MEK inhibitor trametinib when used in combination in soft tissue sarcomas. In RAS mutant models, combination treatment with palbociclib and trametinib induced significant G1 cell cycle arrest, resulting in a marked reduction in cell proliferation and growth. CRISPR-mediated RB1 depletion resulted in a decreased response to CDK4/6 and MEK inhibition, which was validated in both cell culture and xenograft models. Beyond its cell cycle inhibitory effects, pathway enrichment analysis revealed the robust activation of interferon pathways upon CDK4/6 and MEK inhibition. This induction of gene expression was associated with the upregulation of retroviral elements. The TBK1(TANK-binding kinase 1) inhibitor GSK8612 selectively blocked the induction of interferon-related genes induced by palbociclib and trametinib treatment, and highlighted the separable epigenetic responses elicited by combined CDK4/6 and MEK inhibition. Together, these findings provide key mechanistic insights into the therapeutic potential of CDK4/6 and MEK inhibition in soft tissue sarcoma.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141988386","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}