MedComm – Oncology最新文献

{"title":"PGE2-EP2/EP4 axis: A new perspective on cancer immunotherapy","authors":"Lin Chen, Yu-Xin Xu, Jian-Liang Zhou","doi":"10.1002/mog2.90","DOIUrl":"https://doi.org/10.1002/mog2.90","url":null,"abstract":"<p>Lacher et al.<span><sup>1</sup></span> in a recent publication in <i>Nature</i>, revealed a crucial mechanism that limits the responsiveness of TCF1<sup>+</sup> tumor-infiltrating lymphocytes (TILs) to interleukin-2 (IL-2), thereby impeding the anti-cancer T cell response derived from these cells. They identified the prostaglandin E<sub>2</sub> (PGE<sub>2</sub>)-EP<sub>2</sub>/EP<sub>4</sub> axis as a molecular target to restore IL-2 responsiveness in anti-cancer TILs, leading to cancer immune control. This study provides critical insights into the molecular interactions that govern TIL functionality and IL-2 responsiveness, which are essential for effective immunotherapy. Moreover, it suggests that therapeutic strategies aimed at inhibiting the PGE<sub>2</sub>-EP<sub>2</sub>/EP<sub>4</sub> axis could enhance the efficacy of IL-2 based immunotherapies, potentially offering a new avenue for cancer treatment, particularly in tumors where TILs are a significant component of the immune response (Figure 1).</p><p>Tumor immunotherapy marks a significant breakthrough in cancer treatment, with research into immune cells and the tumor microenvironment (TME) uncovering various regulatory factors that influence immune cell activity within tumors. Tumor-derived PGE<sub>2</sub> plays a crucial role in tumor immune evasion and acts as a key inflammatory mediator. Previous studies have shown that PGE<sub>2</sub> affects immune cell activity, function, and metabolism, impacting their ability to recognize and target tumors.<span><sup>2-4</sup></span> This regulatory role of PGE<sub>2</sub> is particularly important for the efficacy of tumor immunotherapy, especially concerning CD8<sup>+</sup> T cells. CD8<sup>+</sup> T cells are vital components of the immune system, responsible for identifying and eliminating tumor cells by recognizing specific antigens on their surfaces. Upon recognition, they release perforins and granzymes to induce apoptosis in tumor cells, contributing to tumor clearance and the success of immunotherapy.<span><sup>5</sup></span> However, the mechanisms by which PGE<sub>2</sub> limits the effector expansion of CD8<sup>+</sup> T cells, particularly in the TME, remain unclear. This study investigates the interaction between PGE<sub>2</sub> and CD8<sup>+</sup> T cells, revealing how PGE<sub>2</sub> restricts the effector expansion of tumor-infiltrating stem-like CD8<sup>+</sup> T cells and its significance in tumor immunotherapy. The findings provide a theoretical basis and clinical guidance for optimizing immunotherapy strategies.</p><p>This study has revealed that tumor-derived PGE<sub>2</sub> significantly inhibits the expansion and effector differentiation of TCF1<sup>+</sup> CD8<sup>+</sup> TILs, which are crucial for sustaining a long-term anti-tumor response. The expansion of these T cells ensures a sufficient quantity of effector cells, while their differentiation into effector cells is essential for directly attacking and eliminatin","PeriodicalId":100902,"journal":{"name":"MedComm – Oncology","volume":"3 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mog2.90","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142234020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deciphering transcriptional bursts and enhancer dynamics: Advancing cancer therapeutics through single-cell global run-on sequencing","authors":"Xiangyu Pan, Feifei Na, Xuelan Chen","doi":"10.1002/mog2.88","DOIUrl":"https://doi.org/10.1002/mog2.88","url":null,"abstract":"<p>The pioneering work of Phillip A. Sharp's research group has led to the development of a cutting-edge single-cell nascent RNA sequencing assay, revolutionizing our understanding of transcription dynamics. The study, published in Nature, incorporates click chemistry into global run-on and sequencing (GRO-seq) to create a single-cell GRO-seq (scGRO-seq) technique.<span><sup>1</sup></span> This method allows for the precise capture of the episodic and coordinated nature of transcription at high resolution, revealing critical dynamics such as burst size and enhancer-gene interactions. Such insights are particularly vital for unraveling the complexities of transcription regulation and cell cycle dynamics across various developmental stages and in the pathological context of diseases like cancer.</p><p>Transcription in development and cancer biology involves short bursts of activity and lengthy silent periods, essential for gene regulation. Core regulatory elements like promoters, transcription factors, and enhancers play key roles in these bursts. Enhancers, specific to cell types and states, regulate genes over long distances and are often linked to disease regions, making them potential targets for cancer therapies.<span><sup>2</sup></span> Current genomic tools provide insights into gene activation precursors but lack real-time transcription event capture. scGRO-seq addresses this gap, offering a dynamic view of regulatory mechanisms for targeted cancer treatment.</p><p>The scGRO-seq technique offers a novel and advanced method for analyzing genome-wide transcription dynamics at a single-cell resolution, filling critical gaps in understanding transcriptional regulation. This method involves labeling nascent RNAs with modified nucleotide triphosphates that contain alkyne groups during a nuclear run-on reaction (Figure 1A). These RNAs are subsequently linked to azide-tagged, single-cell barcode DNA molecules through copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC), known for its efficiency and robustness.<span><sup>3</sup></span> This process not only preserves the integrity of the nuclear membrane but also selectively enriches nascent RNA. Postreaction, these barcoded RNAs are pooled, reverse-transcribed, and PCR amplified to construct a sequencing library, which is then used to detail transcriptional activity within individual cells (Figure 1A).</p><p>The scGRO-seq method has revolutionized the understanding of transcriptional dynamics by refining the approach to detect transcription bursts. Focusing on a 10 kb central gene region and excluding the ends with paused polymerases, it utilizes an RNA Polymerase II elongation rate of 2.5 kb/min, limiting the burst detection window to just 4 min. This setup enables precise measurement of burst sizes, which range from 1 to 4 RNA polymerases, with an average of 1.23, and a mean interval between bursts that aligns with the previously reported 2-h global nascent transcription cycle by intron seqFISH","PeriodicalId":100902,"journal":{"name":"MedComm – Oncology","volume":"3 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mog2.88","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142165391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CoCl2-induced glioma hypoxia environment enhances CD47-SIRPα to promote tumor immune evasion","authors":"Xiangfei Ding,&nbsp;Jianbing Hou,&nbsp;Xiaosong Hu,&nbsp;Wen Peng,&nbsp;Yongsen Li,&nbsp;Gaichao Zhao,&nbsp;Hongjuan Cui,&nbsp;Zonghui Wu,&nbsp;Ping Liang","doi":"10.1002/mog2.87","DOIUrl":"https://doi.org/10.1002/mog2.87","url":null,"abstract":"<p>Elevated levels of tumor-associated macrophages and microglia in the immune microenvironment of malignant gliomas promote tumor growth and progression. Although immune evasion has been implicated in these processes, the mechanisms underlying the regulation of CD47-SIRPα-mediated immune evasion under hypoxic conditions remain unclear. Therefore, this study aimed to explore the mechanisms through which CD47-SIRPα modulates immune evasion in a cobalt chloride (CoCl₂)-induced hypoxic microenvironment of malignant gliomas. Human and mouse glioma cell lines were used to investigate immune evasion in vitro. After membrane protein extraction and nucleoplasmic isolation, we downregulated the expression levels of transport receptors to elucidate the regulation of CD47-SIRPα transport. The CoCl₂-induced hypoxic microenvironment attenuated microglial phagocytosis in glioma cells. Enhanced CD47-SIRPα interaction promoted immune evasion, which negatively affected tumor clearance. In addition, the intracellular transport of CD47 was promoted in the CoCl₂-induced hypoxic state. This process was regulated by regulator of chromosome condensation 1 (RCC1) and sortilin in the nuclear cytoplasm and cytoplasmic membrane, respectively. These results demonstrate the CD47-SIRPα-mediated immune escape mechanism of the CoCl₂-induced glioma hypoxic environment, which is associated with enhanced intracellular transport of CD47. Our findings provide a theoretical basis for the potential development of novel therapies targeting CD47-SIRPα.</p>","PeriodicalId":100902,"journal":{"name":"MedComm – Oncology","volume":"3 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mog2.87","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142077784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The prognostic value of microRNA-200 family expression in digestive system tumors: A meta-analysis and validation","authors":"Xiaoshuang Wu,&nbsp;Jinghua Heng,&nbsp;Mengxiang Li,&nbsp;Danxia Deng,&nbsp;Bingli Wu,&nbsp;Muting Wang,&nbsp;Sanqiang Li,&nbsp;Shegan Gao,&nbsp;Yijun Qi,&nbsp;Enmin Li","doi":"10.1002/mog2.86","DOIUrl":"https://doi.org/10.1002/mog2.86","url":null,"abstract":"<p>The relevance of miR-200 family in the prognosis of digestive system tumors remains controversial. Through a systematic review of the pertinent literature using online databases including PubMed, EMBASE, The Cochrane Library, and Web of Science, our pooled-analysis revealed that miR-200 family downregulation was significantly correlated with poor overall survival (OS, hazard ratio [HR] &gt; 1) and disease-free survival (HR &gt; 1) in digestive malignancies. Consistently, subgroup analyzes of various organ tissues, univariate analysis, gastric cancer, pancreatic cancer, and patients of American descent revealed the hazardous effects of miR-200 family downregulation. In contrast, low miR-200 family expression in blood samples predicted favorable OS (HR &lt; 1). Moreover, lower expression levels of miR-200c-5p and miR-429 were validated in esophageal squamous cell carcinoma (ESCC) tissues. Both the protein and messenger RNA expression levels of Paralemmin-2 (PALM2) and Mitotic Arrest Deficient 2-Like Protein (MAD2L1), regulated by miR-200c-5p, were notably higher in ESCC, and increased protein levels of PALM2 and MAD2L1 were correlated with adverse OS. PALM2 overexpression significantly enhanced ESCC cell migration. In conclusion, our study highlights the prognostic value of miR-200 family in digestive system tumors, and the decrease of miR-200c-5p may promote ESCC invasion through upregulation of PALM2 and MAD2L1.</p>","PeriodicalId":100902,"journal":{"name":"MedComm – Oncology","volume":"3 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mog2.86","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142013527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhancing cancer immunotherapy and antiangiogenic therapy by regulating gut microbes: Opportunities and challenges","authors":"Jie Xu,&nbsp;Yaomei Tian,&nbsp;Die Hu,&nbsp;Xi Yan,&nbsp;Li Yang","doi":"10.1002/mog2.85","DOIUrl":"10.1002/mog2.85","url":null,"abstract":"<p>As the largest microecosystem in the human body, gut microbes (GMs) and their metabolites play an important role in regulating human health. In recent years, immune checkpoint therapy (ICT) combined with antiangiogenic agents is an emerging combination therapy for cancer. There is growing evidence that GMs can affect the effectiveness of drugs to treat cancer. GMs not only regulate angiogenesis in the tumor microenvironment, but also influence the efficacy of immune checkpoint inhibitors. Many studies show that <i>Bifidobacterium</i> can upregulate the anticancer function of immune checkpoint blockers. In addition, GMs have been found to be involved in the formation of blood vessels and other developmental processes. Clinically, GMs are believed to play a key role in patients receiving antiangiogenic therapy and ICT. In this perspective, we provide an overview of the composition and function of the gut microbiome, and discuss the role of the GMs against the conditioning of angiogenic therapy and ICT. We also summarize new approaches and clinical translational trials using GMs for cancer therapy, and present opportunities and challenges for targeting GMs for cancer therapy in the future.</p>","PeriodicalId":100902,"journal":{"name":"MedComm – Oncology","volume":"3 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mog2.85","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141926024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early prediction of neoadjuvant chemotherapy efficacy for mass breast cancer based on dynamic contrast-enhanced magnetic resonance imaging radiomics","authors":"Pei-Wei Cao,&nbsp;Xue-Ying Deng,&nbsp;Yue-Peng Pan,&nbsp;Shuai-Ming Nan,&nbsp;Chang Yu","doi":"10.1002/mog2.84","DOIUrl":"https://doi.org/10.1002/mog2.84","url":null,"abstract":"<p>Radiomics uses automated algorithms to extract high-order features from images, which can contribute to clinical decisions such as therapeutic efficacy evaluation. We assessed the value of a dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI)-based radiomics model for predicting pathological complete response (pCR) after a second cycle of neoadjuvant chemotherapy (NAC) in patients with mass breast cancer. We retrospectively analyzed data from 149 patients with mass breast cancer who underwent NAC between January 2017 and December 2022. Using DCE-MRI, before NAC and after a second cycle of NAC, the least absolute shrinkage and selection operator and logistic regression (LR) algorithms were applied for feature selection and radiomics modeling. We found significant differences in two clinical imaging features (molecular subtypes, background parenchymal enhancement changes) and two radiomics features. Clinical and radiomics features were employed to build clinical, radiomics, and combined models to predict pCR. The LR model that combined clinical and radiomics features had an area under the curve of 0.811, higher than that for the imaging or radiomics model. Our findings suggest that a combined model based on imaging and radiomics features can improve early prediction of NAC efficacy for patients with mass breast cancer.</p>","PeriodicalId":100902,"journal":{"name":"MedComm – Oncology","volume":"3 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mog2.84","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141968284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alanyl-tRNA synthetase AARS1: A novel lactate sensor and lactyltransferase mediating p53 lactylation and tumorigenesis","authors":"Qiqing Yang,&nbsp;Heyu Li,&nbsp;Long Zhang","doi":"10.1002/mog2.83","DOIUrl":"10.1002/mog2.83","url":null,"abstract":"<p>In a recent study published in <i>Cell</i>, Zong et al. discovered that alanyl-tRNA synthetase 1 (AARS1) senses the accumulated lactate and subsequently facilitates global lysine lactylation in tumor cells.<span>¹</span> Furthermore, they found that p53 is a crucial target protein of AARS1-mediated lactylation. Due to the structural similarity between lactate and <span>l</span>-alanine, AARS1 has the capability to directly bind to lactate and transfer it to the K120 and K139 residues of p53 under conditions involving ATP consumption. The lactylation of p53 impairs its DNA binding, liquid–liquid phase separation (LLPS), and transcriptional activation ability, ultimately promoting cancer progression. Additionally, the study revealed that β-alanine inhibits the binding of AARS1 to lactate, suggesting potential implications for cancer treatment. This study identified a novel lactate sensor and lactyltransferase, opening new avenues for furture research on lactylation.</p><p>In 2019, Zhang et al. reported that lactate, which is a byproduct of glycolysis, can modify histones by lactylation.<span>²</span> The Warburg effect explains how the tumor cells rely on glycolysis as the primary energy source, causing accumulation of high lactate levels. Besides, the acidic intratumoral environment causes protein lactylation, ultimately altering the functions of many proteins, promoting cancer progression. As our understanding of lactylation has increased, numerous “readers” and “erasers” of lactylation have been identified.<span>^{3, 4}</span> However, few “writers” of lactylation have been reported. In an effort to fill this gap in knowledge, Zong et al. discovered AARS1 as a novel lactyltransferase responsible for mediating global lactylation in cancer cells. Their findings highlight how AARS1 links cell metabolism with proteome alteration and plays a role in regulating carcinogenesis. Overall, this study shed light on the intricate relationship between energy metabolism and protein lactylation in cancer cells and provide valuable insights into potential targets for cancer therapeutic intervention.</p><p>When evaluating the TCGA breast cancer data set, Zong et al. found that intratumoral lactate may inhibit p53 functions. Furthermore, intratumoral lactate accumulation was closely associated with cancer progression in a mouse model of mammary tumor virus-polyoma middle T antigen transgenic breast cancer. To investigate the role of lactate in vivo, Zong et al. injected mice intraperitoneally with sodium lactate and observed that p53 activity was significantly inhibited in cancer cells. Moreover, knocking out lactate dehydrogenase A in mice resulted in reduced levels of intratumoral lactate and increased p53 activity. To determine whether lactate directly antagonized p53 functions in vitro, Zong et al. used a cell-free system based on luciferase fragment complementation assay to measure p53 activity. They found that tumor cells co","PeriodicalId":100902,"journal":{"name":"MedComm – Oncology","volume":"3 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mog2.83","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141807227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Next-generation sequencing identifies that protein tyrosine phosphatase receptor type D mutation is favorable to immunotherapy in human cancer","authors":"Yongsheng Huang,&nbsp;Jianwei Liao,&nbsp;Ming Gao,&nbsp;Sha Fu,&nbsp;Faya Liang,&nbsp;Yuanling Jiang,&nbsp;Jiahuan Luo,&nbsp;Jinghua Huang,&nbsp;Ni Tan,&nbsp;Danlan Wang,&nbsp;Xinke Yin,&nbsp;Shuwei Ren,&nbsp;Peiliang Lin,&nbsp;Renhui Chen,&nbsp;Ping Han,&nbsp;Xiaoming Huang,&nbsp;Nengtai Ouyang","doi":"10.1002/mog2.80","DOIUrl":"https://doi.org/10.1002/mog2.80","url":null,"abstract":"<p>Protein tyrosine phosphatase receptors (PTPRs) play a crucial part in numerous tumor processes. However, the effect of PTPR mutations on the immune checkpoint inhibitor (ICI) response needs to be further clarified. Next-generation sequencing was performed on 453 cancer patients in our internal cohort. The genomic alterations, tumor mutation burden (TMB), neoantigens, and immune-related features/pathways of other cohorts were analyzed. Here, protein tyrosine phosphatase receptor type D (PTPRD) has a high mutation frequency and an intensified co-occurrence with other PTPRs. Patients who responded to ICI therapy were enriched with the PTPRD mutation (PTPRD-MUT). PTPRD-MUT patients had a higher objective response rate (44.1% vs. 29.1%), TMB/neoantigens, and longer overall survival time than PTPRD-wild-type (PTPRD-WT) patients. Genomic alterations with a higher mutation frequency of genes (such as LRP1B) were enriched in PTPRD-MUT patients. More abundant immune cells (including CD8⁺ T cells and macrophages) and upregulated immune-related genes were found in PTPRD-MUT patients. Moreover, Gene sets enrichment analyses showed that multiple antitumor immune pathways are activated in PTPRD-MUT patients. Therefore, PTPRD-MUT is beneficial for immunotherapy of multiple cancer types and may be a predictive biomarker of patient clinical outcomes.</p>","PeriodicalId":100902,"journal":{"name":"MedComm – Oncology","volume":"3 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mog2.80","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141565746","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical homologous recombination repair gene reversion analysis identifies mechanisms of resistance to PARP inhibitors and platinum-chemotherapy","authors":"Yan Jia,&nbsp;Qiong Yang,&nbsp;Yutong Ma,&nbsp;Miaofang Wu,&nbsp;Qiuxiang Ou,&nbsp;Zhongqiu Lin,&nbsp;Yunyu Wu,&nbsp;Jing Li","doi":"10.1002/mog2.79","DOIUrl":"https://doi.org/10.1002/mog2.79","url":null,"abstract":"<p>Identifying mechanisms underlying cancer resistance to therapy is vital for advancing treatment strategies. Pathogenic mutations of homologous recombination repair (HRR) genes are known biomarkers for platinum (Pt)-based chemotherapy and poly ADP ribose polymerase inhibitors (PARPi) effectiveness. Yet, the dynamics of HRR reversion mutations, which may herald therapy resistance, are not fully elucidated. Addressing this gap, our study analyzed secondary HRR gene mutations in a comprehensive pan-cancer data set of approximately 13,000 patients who underwent targeted next-generation sequencing. We identified a subset of patients harboring secondary mutations, which were further categorized into three tiers based on their nature, and occur in the presence of a primary pathogenic mutation, notably in <i>BRCA1</i>, <i>BRCA2</i>, <i>PALB2</i>, and <i>RAD51D</i> genes. Here we show that secondary <i>BRCA2</i> mutations, indicative of adaptive resistance, emerge post-Pt/Olaparib treatment. This challenges the prevailing notion that pathogenic HRR mutations uniformly predict therapeutic sensitivity, highlighting a nuanced genetic interplay that impacts treatment success. This investigation enriches our understanding of cancer's adaptive mechanisms against therapy, suggesting a pivotal shift towards more personalized, dynamic treatment strategies. It underscores the imperative of adapting to cancer's genetic evolution, aiming for a step ahead in the ongoing battle against this disease.</p>","PeriodicalId":100902,"journal":{"name":"MedComm – Oncology","volume":"3 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mog2.79","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141488702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting werner helicase with synthetic lethality in microsatellite instability cancers: Promising therapeutic approaches","authors":"Huanzhang Xie,&nbsp;Jing Zhang","doi":"10.1002/mog2.82","DOIUrl":"https://doi.org/10.1002/mog2.82","url":null,"abstract":"<p>Two recent companion papers published in Nature have reported two promising drug candidates, HRO761<span>¹</span> and VVD-133214,<span>²</span> for microsatellite instability (MSI) cancers targeting the werner syndrome RecQ helicase (WRN), a synthetic lethal target in cancer cells with MSI. Currently, both candidates are undergoing clinical trials to evaluate their safety, tolerability, and preliminary antitumor activity in MSI patients.</p><p>Microsatellites, also known as short tandem repeats, are susceptible to slippage errors during replication, rendering them heavily reliant on the DNA mismatch repair (MMR) system. MMR deficiency results in widespread MSI by failing to correct replication errors, thus initiating cancer via aberrant tumor suppressor gene function. The prevalence of MSI ranges from 10% to 30% across multiple cancer types, such as colorectal, endometrial, ovarian, and gastric cancers.<span>^1-3</span> In MSI tumors, deficiencies in MMR mechanisms heighten genomic instability, prompting the activation of alternative DNA repair pathways, including those implicating WRN. Inhibitors targeting WRN in MSI cancer cells, which already possess compromised DNA repair mechanisms, may induce synthetic lethality, thereby triggering DNA damage and subsequent cancer cell death. This targeted approach is ineffective against normal or microsatellite instability (MSS) cells, as their MMR mechanisms remain intact. Hence, WRN inhibitors emerge as a highly promising synthetic lethal agent, with the potential to selectively eradicate tumor cells while sparing normal cells (Figure 1A).</p><p>Novartis researchers reported HRO761,<span>¹</span> a novel WRN helicase inhibitor (Figure 1B) which targets the ATPase of WRN as a noncovalent inhibitor. Cocrystal structures of HRO761 with WRN helicase revealed its binding to a nonconserved site at the D1–D2 interface, immobilizing WRN in an inactive conformation with an approximate 180° rotation relative to the adenosine triphosphate (ATP)-bound conformation (Figure 1C). Despite its 702 Da molecular weight, HRO761 displayed favorable physicochemical properties and pharmacokinetics (PK), with a clean off-target profile. In vitro cellular assays showed that HRO761 exhibits an IC₅₀ of 100 nM in ATPase assays at high ATP concentration, effectively impairing the viability of MSI cancer cells, while showing no effect in MSS cells. Furthermore, characterization of HRO761 treatment effects on MSI cells revealed time- and dose-dependent cell cycle arrest and DNA damage, regardless of p53 mutation status. In the SW48 cell-derived xenografts (CDX) model, oral administration of 15–60 mg/kg HRO761 resulted in significant tumor regression without observed toxicity. Additionally, combination therapy involving HRO761 with other antitumor drugs may enhance treatment efficacy and reduce side effects and resistance. In vivo studies show complete tumor regression with combi","PeriodicalId":100902,"journal":{"name":"MedComm – Oncology","volume":"3 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mog2.82","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141315451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}