Cancer research最新文献

{"title":"KRAS Loss of Heterozygosity Promotes MAPK-Dependent Pancreatic Ductal Adenocarcinoma Initiation and Induces Therapeutic Sensitivity to MEK Inhibition","authors":"Sigrid K. Fey, Arafath K. Najumudeen, Dale M. Watt, Laura M. Millett, Catriona A. Ford, Kathryn Gilroy, Rosalin J. Simpson, Kathy McLay, Rosanna Upstill-Goddard, David Chang, William Clark, Colin Nixon, Joanna L. Birch, Simon T. Barry, Jennifer P. Morton, Andrew D. Campbell, Owen J. Sansom","doi":"10.1158/0008-5472.can-23-2709","DOIUrl":"https://doi.org/10.1158/0008-5472.can-23-2709","url":null,"abstract":"Pancreatic cancer is characterized by the prevalence of oncogenic mutations in KRAS. Previous studies have reported that altered KRAS gene dosage drives progression and metastasis in pancreatic cancer. While the role of oncogenic KRAS mutations is well characterized, the relevance of the partnering wild-type KRAS allele in pancreatic cancer is less well understood and controversial. Using in vivo mouse modelling of pancreatic cancer, we demonstrated that wild-type KRAS restrains the oncogenic impact of mutant KRAS and dramatically impacts both KRAS-mediated tumorigenesis and therapeutic response. Mechanistically, deletion of wild-type Kras increased oncogenic KRAS signaling through the downstream MAPK effector pathway, driving pancreatic intraepithelial neoplasia (PanIN) initiation. In addition, in the KPC mouse model, a more aggressive model of pancreatic cancer, lack of wild-type KRAS led to accelerated initiation but delayed tumor progression. These tumors had altered stroma and an enrichment of immunogenic gene signatures. Importantly, loss of wild-type Kras sensitized Kras mutant tumors to MEK1/2 inhibition though tumors eventually became resistant and then rapidly progressed. This study demonstrates the repressive role of wild-type KRAS during pancreatic tumorigenesis and highlights the critical impact of the presence of wild-type KRAS in both tumor progression and therapeutic response in pancreatic cancer.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"73 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142444236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting the Sodium-Potassium Pump as a Therapeutic Strategy in Acute Myeloid Leukemia.","authors":"Constanze Schneider, Hermes Spaink, Gabriela Alexe, Neekesh V Dharia, Ashleigh Meyer, Lucy A Merickel, Delan Khalid, Sebastian Scheich, Björn Häupl, Louis M Staudt, Thomas Oellerich, Kimberly Stegmaier","doi":"10.1158/0008-5472.CAN-23-3560","DOIUrl":"10.1158/0008-5472.CAN-23-3560","url":null,"abstract":"<p><p>Tissue-specific differences in the expression of paralog genes, which are not essential in most cell types due to the buffering effect of the partner pair, can make for highly selective gene dependencies. To identify selective paralogous targets for acute myeloid leukemia (AML), we integrated the Cancer Dependency Map with numerous datasets characterizing protein-protein interactions, paralog relationships, and gene expression in cancer models. In this study, we identified ATP1B3 as a context-specific, paralog-related dependency in AML. ATP1B3, the β-subunit of the sodium-potassium pump (Na/K-ATP pump), interacts with the α-subunit ATP1A1 to form an essential complex for maintaining cellular homeostasis and membrane potential in all eukaryotic cells. When ATP1B3's paralog ATP1B1 is poorly expressed, elimination of ATP1B3 leads to the destabilization of the Na/K-ATP pump. ATP1B1 expression is regulated through epigenetic silencing in hematopoietic lineage cells through histone and DNA methylation in the promoter region. Loss of ATP1B3 in AML cells induced cell death in vitro and reduced leukemia burden in vivo, which could be rescued by stabilizing ATP1A1 through overexpression of ATP1B1. Thus, ATP1B3 is a potential therapeutic target for AML and other hematologic malignancies with low expression of ATP1B1. Significance: ATP1B3 is a lethal selective paralog dependency in acute myeloid leukemia that can be eliminated to destabilize the sodium-potassium pump, inducing cell death.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"3354-3370"},"PeriodicalIF":12.5,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11479832/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141723118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retraction: Differential Effects of VEGFR-1 and VEGFR-2 Inhibition on Tumor Metastases Based on Host Organ Environment.","authors":"Yoon-Jin Lee, Daniel L Karl, Ugwuji N Maduekwe, Courtney Rothrock, Sandra Ryeom, Patricia A D'Amore, Sam S Yoon","doi":"10.1158/0008-5472.CAN-24-3248","DOIUrl":"10.1158/0008-5472.CAN-24-3248","url":null,"abstract":"","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"84 20","pages":"3490"},"PeriodicalIF":12.5,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11577321/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142458688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Natural Killer Cell Regulation of Breast Cancer Stem Cells Mediates Metastatic Dormancy.","authors":"Grace G Bushnell, Deeksha Sharma, Henry C Wilmot, Michelle Zheng, Toluwaleke D Fashina, Chloe M Hutchens, Samuel Osipov, Monika Burness, Max S Wicha","doi":"10.1158/0008-5472.CAN-24-0030","DOIUrl":"10.1158/0008-5472.CAN-24-0030","url":null,"abstract":"<p><p>Patients with breast cancer with estrogen receptor-positive tumors face a constant risk of disease recurrence for the remainder of their lives. Dormant tumor cells residing in tissues such as the bone marrow may generate clinically significant metastases many years after initial diagnosis. Previous studies suggest that dormant cancer cells display \"stem-like\" properties (cancer stem cell, CSC), which may be regulated by the immune system. To elucidate the role of the immune system in controlling dormancy and its escape, we studied dormancy in immunocompetent, syngeneic mouse breast cancer models. Three mouse breast cancer cell lines, PyMT, Met1, and D2.0R, contained CSCs that displayed short- and long-term metastatic dormancy in vivo, which was dependent on the host immune system. Each model was regulated by different components of the immune system. Natural killer (NK) cells were key for the metastatic dormancy phenotype in D2.0R cells. Quiescent D2.0R CSCs were resistant to NK cell cytotoxicity, whereas proliferative CSCs were sensitive. Resistance to NK cell cytotoxicity was mediated, in part, by the expression of BACH1 and SOX2 transcription factors. Expression of STING and STING targets was decreased in quiescent CSCs, and the STING agonist MSA-2 enhanced NK cell killing. Collectively, these findings demonstrate the role of immune regulation of breast tumor dormancy and highlight the importance of utilizing immunocompetent models to study this phenomenon. Significance: The immune system controls disseminated breast cancer cells during disease latency, highlighting the need to utilize immunocompetent models to identify strategies for targeting dormant cancer cells and reducing metastatic recurrence. See related commentary by Cackowski and Korkaya, p. 3319.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"3337-3353"},"PeriodicalIF":12.5,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11474167/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141896779","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor's Digest: Macrophage Metabolism Creates a Barrier to T Cells.","authors":"Elly J Tyler, Oliver M T Pearce","doi":"10.1158/0008-5472.CAN-24-3039","DOIUrl":"10.1158/0008-5472.CAN-24-3039","url":null,"abstract":"<p><p>Changes in the composition and physical properties of the tumor extracellular matrix are linked to poor cytotoxic T-cell infiltration and therapy response, yet the underlying mechanisms remain unclear. Tharp and colleagues revealed a fascinating cascade where tumor fibrosis alters macrophage metabolism, restricting the nutrients available to infiltrating T cells and resulting in their suppression and exclusion from the tumor microenvironment. This study suggests that targeting metabolic pathways could be a promising strategy to overcome the immune suppression induced by the tumor extracellular matrix.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"3322-3323"},"PeriodicalIF":12.5,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142072102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-Stranded DNA Gap Accumulation Is a Functional Biomarker for USP1 Inhibitor Sensitivity.","authors":"Alexandre A da Costa, Ozge Somuncu, Ramya Ravindranathan, Sirisha Mukkavalli, David B Martignetti, Huy Nguyen, Yuqing Jiao, Benjamin P Lamarre, Golbahar Sadatrezaei, Lisa Moreau, Joyce Liu, Divya R Iyer, Jean-Bernard Lazaro, Geoffrey I Shapiro, Kalindi Parmar, Alan D D'Andrea","doi":"10.1158/0008-5472.CAN-23-4007","DOIUrl":"10.1158/0008-5472.CAN-23-4007","url":null,"abstract":"<p><p>Recent studies suggest that PARP and POLQ inhibitors confer synthetic lethality in BRCA1-deficient tumors by accumulation of single-stranded DNA (ssDNA) gaps at replication forks. Loss of USP1, a deubiquitinating enzyme, is also synthetically lethal with BRCA1 deficiency, and USP1 inhibitors are now undergoing clinical development for these cancers. Herein, we show that USP1 inhibitors also promote the accumulation of ssDNA gaps during replication in BRCA1-deficient cells, and this phenotype correlates with drug sensitivity. USP1 inhibition increased monoubiquitinated proliferating cell nuclear antigen at replication forks, mediated by the ubiquitin ligase RAD18, and knockdown of RAD18 caused USP1 inhibitor resistance and suppression of ssDNA gaps. USP1 inhibition overcame PARP inhibitor resistance in a BRCA1-mutated xenograft model and induced ssDNA gaps. Furthermore, USP1 inhibition was synergistic with PARP and POLQ inhibition in BRCA1-mutant cells, with enhanced ssDNA gap accumulation. Finally, in patient-derived ovarian tumor organoids, sensitivity to USP1 inhibition alone or in combination correlated with the accumulation of ssDNA gaps. Assessment of ssDNA gaps in ovarian tumor organoids represents a rapid approach for predicting response to USP1 inhibition in ongoing clinical trials. Significance: USP1 inhibitors kill BRCA1-deficient cells and cause ssDNA gap accumulation, supporting the potential of using ssDNA gap detection as a functional biomarker for clinical trials on USP1 inhibitors.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"3435-3446"},"PeriodicalIF":12.5,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11474172/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141417940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chromosome 7 Gain Compensates for Chromosome 10 Loss in Glioma.","authors":"Nishanth Ulhas Nair, Alejandro A Schäffer, E Michael Gertz, Kuoyuan Cheng, Johanna Zerbib, Avinash Das Sahu, Gil Leor, Eldad D Shulman, Kenneth D Aldape, Uri Ben-David, Eytan Ruppin","doi":"10.1158/0008-5472.CAN-24-1366","DOIUrl":"10.1158/0008-5472.CAN-24-1366","url":null,"abstract":"<p><p>The co-occurrence of chromosome 10 loss and chromosome 7 gain in gliomas is the most frequent loss-gain co-aneuploidy pair in human cancers. This phenomenon has been investigated since the late 1980s without resolution. Expanding beyond previous gene-centric studies, we investigated the co-occurrence in a genome-wide manner, taking an evolutionary perspective. Mining of large-scale tumor aneuploidy data confirmed the previous finding of a small-scale longitudinal study that the most likely order is chromosome 10 loss, followed by chromosome 7 gain. Extensive analysis of genomic and transcriptomic data from both patients and cell lines revealed that this co-occurrence can be explained by functional rescue interactions that are highly enriched on chromosome 7, which could potentially compensate for any detrimental consequences arising from the loss of chromosome 10. Transcriptomic data from various normal, noncancerous human brain tissues were analyzed to assess which tissues may be most predisposed to tolerate compensation of chromosome 10 loss by chromosome 7 gain. The analysis indicated that the preexisting transcriptomic states in the cortex and frontal cortex, where gliomas arise, are more favorable than other brain regions for compensation by rescuer genes that are active on chromosome 7. Collectively, these findings suggest that the phenomenon of chromosome 10 loss and chromosome 7 gain in gliomas is orchestrated by a complex interaction of many genes residing within these two chromosomes and provide a plausible reason why this co-occurrence happens preferentially in cancers originating in certain regions of the brain.  Significance: Increased expression of multiple rescuer genes on the gained chromosome 7 could compensate for the downregulation of several vulnerable genes on the lost chromosome 10, resolving the long-standing mystery of this frequent co-occurrence in gliomas.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"3464-3477"},"PeriodicalIF":12.5,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11479827/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141792018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retraction: Variable Inhibition of Thrombospondin 1 against Liver and Lung Metastases through Differential Activation of Metalloproteinase ADAMTS1.","authors":"Yoon-Jin Lee, Moritz Koch, Daniel Karl, Antoni X Torres-Collado, Namali T Fernando, Courtney Rothrock, Darshini Kuruppu, Sandra Ryeom, M Luisa Iruela-Arispe, Sam S Yoon","doi":"10.1158/0008-5472.CAN-24-3247","DOIUrl":"10.1158/0008-5472.CAN-24-3247","url":null,"abstract":"","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"84 20","pages":"3491"},"PeriodicalIF":12.5,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11574747/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142458689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An Alternatively Spliced Gain-of-Function NT5C2 Isoform Contributes to Chemoresistance in Acute Lymphoblastic Leukemia.","authors":"Manuel Torres-Diz, Clara Reglero, Catherine D Falkenstein, Annette Castro, Katharina E Hayer, Caleb M Radens, Mathieu Quesnel-Vallières, Zhiwei Ang, Priyanka Sehgal, Marilyn M Li, Yoseph Barash, Sarah K Tasian, Adolfo Ferrando, Andrei Thomas-Tikhonenko","doi":"10.1158/0008-5472.CAN-23-3804","DOIUrl":"10.1158/0008-5472.CAN-23-3804","url":null,"abstract":"<p><p>Relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL) is a major cause of pediatric cancer-related deaths. Relapse-specific mutations do not account for all chemotherapy failures in B-ALL patients, suggesting additional mechanisms of resistance. By mining RNA sequencing datasets of paired diagnostic/relapse pediatric B-ALL samples, we discovered pervasive alternative splicing (AS) patterns linked to relapse and affecting drivers of resistance to glucocorticoids, antifolates, and thiopurines. Most splicing variations represented cassette exon skipping, \"poison\" exon inclusion, and intron retention, phenocopying well-documented loss-of-function mutations. In contrast, relapse-associated AS of NT5C2 mRNA yielded an isoform with the functionally uncharacterized in-frame exon 6a. Incorporation of the 8-amino acid sequence SQVAVQKR into this enzyme created a putative phosphorylation site and resulted in elevated nucleosidase activity, which is a known consequence of gain-of-function mutations in NT5C2 and a common determinant of 6-mercaptopurine resistance. Consistent with this finding, NT5C2ex6a and the R238W hotspot variant conferred comparable levels of resistance to 6-mercaptopurine in B-ALL cells both in vitro and in vivo. Furthermore, both NT5C2ex6a and the R238W variant induced collateral sensitivity to the inosine monophosphate dehydrogenase inhibitor mizoribine. These results ascribe to splicing perturbations an important role in chemotherapy resistance in relapsed B-ALL and suggest that inosine monophosphate dehydrogenase inhibitors, including the commonly used immunosuppressive agent mycophenolate mofetil, could be a valuable therapeutic option for treating thiopurine-resistant leukemias. Significance: Alternative splicing is a potent mechanism of acquired drug resistance in relapsed/refractory acute lymphoblastic leukemias that has diagnostic and therapeutic implications for patients who lack mutations in known chemoresistance genes.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"3327-3336"},"PeriodicalIF":12.5,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11474164/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141878430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The USP1 Inhibitor KSQ-4279 Overcomes PARP Inhibitor Resistance in Homologous Recombination-Deficient Tumors.","authors":"Louise Cadzow,Jehrod Brenneman,Erica Tobin,Pamela Sullivan,Sumeet Nayak,Janid A Ali,Sol Shenker,Jim Griffith,Michael McGuire,Paula Grasberger,Yuji Mishina,Morgan Murray,Anne E Dodson,Hugh Gannon,Elsa Krall,Jeff Hixon,Edmond Chipumuro,Kerstin Sinkevicius,Prafulla C Gokhale,Suthakar Ganapathy,Ursula A Matulonis,Joyce F Liu,Andrew Olaharski,Dipen Sangurdekar,Hanlan Liu,Jeremy Wilt,Michael Schlabach,Frank Stegmeier,Andrew A Wylie","doi":"10.1158/0008-5472.can-24-0293","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-0293","url":null,"abstract":"Defects in DNA repair pathways play a pivotal role in tumor evolution and resistance to therapy. At the same time, they create vulnerabilities that render tumors dependent on the remaining DNA repair processes. This phenomenon is exemplified by the clinical activity of PARP inhibitors in tumors with homologous recombination (HR) repair defects, such as tumors with inactivating mutations in BRCA1 or BRCA2. However, the development of resistance to PARP inhibitors in BRCA-mutant tumors represents a high unmet clinical need. In this study, we identified deubiquitinase ubiquitin-specific peptidase-1 (USP1) as a critical dependency in tumors with BRCA mutations or other forms of HR deficiency and developed KSQ-4279, the first potent and selective USP1 inhibitor to enter clinical testing. The combination of KSQ-4279 with a PARP inhibitor was well tolerated and induced durable tumor regression across several patient-derived PARP-resistant models. These findings indicate that USP1 inhibitors represent a promising therapeutic strategy for overcoming PARP inhibitor resistance in patients with BRCA-mutant/HR-deficient tumors and support continued testing in clinical trials. Significance: KSQ-4279 is a potent and selective inhibitor of USP1 that induces regression of PARP inhibitor-resistant tumors when dosed in combination with PARP inhibitors, addressing an unmet clinical need for BRCA-mutant tumors.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"10 1","pages":"3419-3434"},"PeriodicalIF":11.2,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142439563","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}