Molecular Cancer Therapeutics最新文献

{"title":"Abstract B017: Loss of UXS1 selectively kills KEAP1 mutant cancer cell lines by depleting pyrimidines and inducing replication stress","authors":"Timothy Hoffman, Melat Gebru, Aaron Boudreau, Fei Han, Kelly Foster-Duke, Jessica Gajda, Ngoc Vu, Bryson D Bennett, Michael Kort, Brad Shotwell, Jonathan Hickson, Noel Wilsomn, David Stokoe","doi":"10.1158/1538-8514.synthleth24-b017","DOIUrl":"https://doi.org/10.1158/1538-8514.synthleth24-b017","url":null,"abstract":"\u0000 Kelch-like ECH Associated-Protein 1 (KEAP1) is the third most mutated gene in non-small cell lung cancer and is associated with poor prognosis. KEAP1 targets nuclear factor erythroid 2-related factor 2 (Nrf2) for degradation, hence KEAP1-mutated tumors have elevated Nrf2 levels and constitutive expression of its transcriptional targets. To identify potential therapeutic targets for KEAP1 mutated tumors, we interrogated the cancer Dependency Map (DepMap) database and identified UDP Xylose Synthase 1 (UXS1) as a synthetic lethal interaction gene in KEAP1 mutated cancer cell lines. UXS1 is a critical protein for the glycosaminoglycan (GAG) synthesis on proteoglycans, converting UDP-glucuronic acid (UDPGA) to UDP-xylose. UDP glucose dehydrogenase (UGDH) is a transcriptional target of Nrf2 highly expressed in KEAP1-mutant tumors, which converts UDP-glucose to UDPGA. Upon UXS1 knock-down, depletion of UDP-xylose is seen in both KEAP1-mutant and wildtype cells, as expected, whereas rapid accumulation of UDPGA is only seen in the KEAP1-mutant setting. This metabolic roadblock causes a shortage of available UDP and other pyrimidines, resulting in slowed S-phase progression, stalled DNA replication fork marks, subsequent DNA damage, and significant loss in cell viability. Notably, dependency on UXS1 can be rescued by either knocking out UGDH to prevent UDPGA accumulation or by supplementation of cells with uridine or cytidine to restore the pyrimidine nucleotide pools by boosting pyrimidine salvage pathway. Finally, we show that DNA replication stress in UXS1-depleted cells renders them sensitive to clinical cell-cycle checkpoint inhibitors, opening a further window of therapeutically exploitable vulnerability.\u0000 Citation Format: Timothy Hoffman, Melat Gebru, Aaron Boudreau, Fei Han, Kelly Foster-Duke, Jessica Gajda, Ngoc Vu, Bryson Bennett, Michael Kort, Brad Shotwell, Jonathan Hickson, Noel Wilsomn, David Stokoe. Loss of UXS1 selectively kills KEAP1 mutant cancer cell lines by depleting pyrimidines and inducing replication stress [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr B017.","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141363127","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":"Abstract IA012: Generation and Mining of a Pediatric-focused Cancer Cell Line Atlas to Define Druggable Genetic Interactions in Childhood Malignancies","authors":"Ron Firestein","doi":"10.1158/1538-8514.synthleth24-ia012","DOIUrl":"https://doi.org/10.1158/1538-8514.synthleth24-ia012","url":null,"abstract":"\u0000 Pediatric solid and central nervous system tumors are the primary cause of cancer-related fatalities in children. Discovering novel targeted therapies requires utilizing pediatric cancer models that accurately mirror the patient's illness. However, the creation and evaluation of these models have significantly trailed adult cancer research, emphasizing the pressing demand for pediatric-centric cell line repositories. Here, we establish a centralized collection of over 450 childhood cancer cell lines. We subjected over 250 of these cell lines to comprehensive multi-omics analyses (including DNA sequencing, RNA sequencing, and DNA methylation analysis), while concurrently conducting pharmacological screenings and genetic CRISPR-Cas9 loss-of-function assays to unveil pediatric-specific treatment avenues and biomarkers. Machine learning approaches were then applied to uncover genotype-phenotype relationships and synthetic lethal interactions. Our endeavor sheds light on the specific vulnerabilities of pathways in molecularly characterized pediatric tumor subclasses and reveals clinically relevant therapeutic opportunities linked with biomarkers. We offer access to the cell line data and resources through an open-access portal.\u0000 Citation Format: Ron Firestein. Generation and Mining of a Pediatric-focused Cancer Cell Line Atlas to Define Druggable Genetic Interactions in Childhood Malignancies [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr IA012.","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141364446","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":"Abstract B018: Investigating vulnerabilities associated with chromosome arm aneuploidy in cancer","authors":"Nadja Zhakula-Kostadinova, Sejal Jain, Laura Byron, Matthew L. Meyerson, Alison M. Taylor","doi":"10.1158/1538-8514.synthleth24-b018","DOIUrl":"https://doi.org/10.1158/1538-8514.synthleth24-b018","url":null,"abstract":"\u0000 This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR016) of the Conference Program/Proceedings.\u0000 Citation Format: Nadja Zhakula-Kostadinova, Sejal Jain, Laura Byron, Matthew L. Meyerson, Alison M. Taylor. Investigating vulnerabilities associated with chromosome arm aneuploidy in cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr B018.","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141363180","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":"Abstract B011: Detecting pairwise and higher-order antagonistic epistatic effects among somatic cancer genotypes to discover synthetic lethality","authors":"Jorge A. Alfaro-Murillo, K. Dasari, Jeffrey P. Townsend","doi":"10.1158/1538-8514.synthleth24-b011","DOIUrl":"https://doi.org/10.1158/1538-8514.synthleth24-b011","url":null,"abstract":"\u0000 This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR013) of the Conference Program/Proceedings.\u0000 Citation Format: Jorge A. Alfaro-Murillo, Krishna Dasari, Jeffrey P Townsend. Detecting pairwise and higher-order antagonistic epistatic effects among somatic cancer genotypes to discover synthetic lethality [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr B011.","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141361061","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":"Abstract PR008: Targeting mechanisms of dosage compensation to selectively kill aneuploid cancer cells","authors":"Hajime Okada, Eran Sdeor, Miriam Karmon, E. Levanon, Uri Ben-David","doi":"10.1158/1538-8514.synthleth24-pr008","DOIUrl":"https://doi.org/10.1158/1538-8514.synthleth24-pr008","url":null,"abstract":"\u0000 Aneuploidy is an abnormal chromosome composition and a general hallmark of human cancer. Aneuploidy causes detrimental cellular stresses, but cancer cells evolve to cope with these stresses. Consequently, targeting such mitigation mechanisms is a promising potential therapeutic strategy. As an abnormal dosage of gene products from altered chromosomes can cause RNA and proteotoxic stress, dosage compensation (DC) of imbalanced gene products was reported to mitigate these stresses in aneuploid cells. However, the mechanisms that regulate DC remain elusive. To address these mechanisms, we focused on the role(s) of stress granules (SGs) and RNA binding proteins (RBPs) in aneuploid cancer cells. Our recent study revealed that aneuploid cancer cells preferentially depend on RNA and protein metabolism, and need to attenuate translation in order to cope with proteotoxic stress (Ippolito & Zerbib et al. bioRxiv 2023). In yeast, it has been previously reported that Ssd1, one of the RBPs localized in P-bodies, is indispensable to tolerating aneuploidy stress. Based on these findings, we set out to explore SGs as potential regulators of gene expression in aneuploid cancer cells. As expected, we revealed that SGs emerged in cells under acute aneuploidy stress induced by chromosome mis-segregation. These results imply that SGs are formed in cells during and right after aneuploidization, potentially as a way to mediate DC and ameliorate aneuploidy-induced cellular stress. To gain further insight into RNA regulation in aneuploid cells, we analyzed the essentiality of RBPs across cancer cell lines. We found that the RNA-editing enzyme ADAR, a suppressor of SG formation, is preferentially essential in aneuploid cancer cells. Remarkably, ADAR disruption synergized with acute aneuploidy stress to induce SGs, and ADAR exhibited increased RNA editing activity following chromosome mis-segregation. Our results suggest that SGs and their suppressor ADAR might contribute to ameliorating acute aneuploidy-induced stress. We are currently investigating the target RNAs regulated by SGs and ADAR and examining their functional role(s) in DC, with the goal of uncovering potential synthetic lethalities associated with aneuploidy in cancer cells.\u0000 Citation Format: Hajime Okada, Eran Sdeor, Miriam Karmon, Erez Levanon, Uri Ben-David. Targeting mechanisms of dosage compensation to selectively kill aneuploid cancer cells [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr PR008.","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141361771","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":"Abstract IA003: Chemoproteomic discovery of a covalent allosteric inhibitor of WRN helicase","authors":"Matt Patricelli, K. Baltgalvis, Kelsey N. Lamb, Kent T. Symons, Chu-Chiao Wu, Melissa A. Hoffman, Aaron N. Snead, Xiaodan Song, Thomas Glaza, S. Kikuchi, Jason C. Green, Donald C. Rogness, Betty Lam, Maria E Rodriguez-Aguirre, David R. Woody, Christie L. Eissler, Socorro Rodilles, Seth M. Negron, Steffen M. Bernard, Eileen Tran, Jonathan Pollock, Ali Tabatabaei, Victor Contreras, Heather N Williams, Martha K. Pastuszka, John J. Sigler, Piergiorgio Pettazzoni, Markus G Rudolph, Moritz Classen, Doris Brugger, Christopher Claiborne, Jean‐Marc Plancher, I. Cuartas, Joan Seoane, Laurence E. Burgess, Robert T. Abraham, David S. Weinstein, Gabe Simon, Todd M Kinsella","doi":"10.1158/1538-8514.synthleth24-ia003","DOIUrl":"https://doi.org/10.1158/1538-8514.synthleth24-ia003","url":null,"abstract":"\u0000 The WRN helicase serves as a key target in the treatment of cancers characterized by microsatellite instability (MSI) because it plays a crucial role in resolving harmful non-canonical DNA structures that arise in cells with defective mismatch repair systems. Despite the critical functions of human DNA and RNA helicases, no drugs targeting these enzymes have been approved, largely due to the difficulties in identifying potent and selective inhibitors. In this study, we present the chemoproteomics-based identification of a clinical-stage, covalent allosteric inhibitor of WRN, VVD-133214. This inhibitor specifically interacts with a cysteine residue (C727) within the helicase domain, which undergoes inter-domain movement during the DNA unwinding process. VVD-133214 reacts with the WRN protein in a nucleotide cooperative manner, promoting stable, compact structures that impede the enzyme's dynamic flexibility essential for its helicase activity. Inhibition of WRN by VVD-133214 leads to extensive double-stranded DNA breaks, nuclear enlargement, and ultimately cell death, specifically in MSI-high cells but not in microsatellite stable cells. The inhibitor demonstrated good tolerance in mice and significant tumor reduction in various MSI-high colorectal cancer cell lines and patient-derived xenograft models. Our findings highlight an allosteric strategy to inhibit WRN function that avoids interference from the endogenous ATP cofactor in cancer cells and positions VVD-133214 as a promising therapeutic candidate for patients with MSI-high cancers.\u0000 Citation Format: Matthew P. Patricelli, Kristen A. Baltgalvis, Kelsey N. Lamb, Kent T. Symons, Chu-Chiao Wu, Melissa A. Hoffman, Aaron N. Snead, Xiaodan Song, Thomas Glaza, Shota Kikuchi, Jason C. Green, Donald C. Rogness, Betty Lam, Maria E. Rodriguez-Aguirre, David R. Woody, Christie L. Eissler, Socorro Rodilles, Seth M .Negron, Steffen M. Bernard, Eileen Tran, Jonathan Pollock, Ali Tabatabaei, Victor Contreras, Heather N Williams, Martha K. Pastuszka, John J. Sigler, Piergiorgio Pettazzoni, Markus G. Rudolph, Moritz Classen, Doris Brugger, Christopher Claiborne, Jean-Marc Plancher, Isabel Cuartas, Joan Seoane, Laurence E. Burgess, Robert T. Abraham, David S. Weinstein, Gabriel M. Simon, Todd M. Kinsella. Chemoproteomic discovery of a covalent allosteric inhibitor of WRN helicase [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr IA003.","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141365072","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":"Abstract IA015: Identifying and targeting synthetic lethalities of aneuploid (cancer) cells","authors":"Uri Ben-David","doi":"10.1158/1538-8514.synthleth24-ia015","DOIUrl":"https://doi.org/10.1158/1538-8514.synthleth24-ia015","url":null,"abstract":"\u0000 Aneuploidy, an imbalanced number of chromosomes or chromosome arms, is a genetic hallmark of cancer cells, yet aneuploidy remains a biological enigma and a missed opportunity for cancer therapy. Aneuploid cells must cope with several types of cellular stresses, potentially creating synthetic lethalities that can be used to target aneuploid cancer cells. Here, I will describe our efforts to identify synthetic lethalities of the aneuploid state (in contrast to synthetic lethalities of specific recurrent aneuploidies. Specifically, I will focus on three recent unpublished studies, where we report that: (1) Aneuploid cells are preferentially sensitive to perturbation of the spindle assembly checkpoint (SAC) and its regulator KIF18A; the expression and activity of CDC20 determine the sensitivity to SAC inhibition. (2) Aneuploid cells depend on MAPK signaling for overcoming aneuploidy-induced DNA damage; targeting MAPK signaling can sensitize aneuploid cells to DNA damage inducing agents and to PARP inhibitors. (3) Aneuploid cells depend on RNA and protein degradation mechanisms to attenuate the cellular consequence of extra chromosomes; this renders aneuploid cells more sensitive to inhibition of nonsense-mediate decay, miRNA-mediated gene silencing, and the proteasome complex.\u0000 Citation Format: Uri Ben-David. Identifying and targeting synthetic lethalities of aneuploid (cancer) cells [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr IA015.","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141362741","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":"Abstract B029: Assessing gene expression and methylation of KMT2D and IGF2 genes in patients with non-small cell lung cancer","authors":"Arash Matinahmadi, Zoofa Zayani, Seyed Hesamoddin Bidooki, Alireza Tavakolpournegari","doi":"10.1158/1538-8514.synthleth24-b029","DOIUrl":"https://doi.org/10.1158/1538-8514.synthleth24-b029","url":null,"abstract":"\u0000 Background: Aberrant promoter methylation of CpG islands is an important mechanism for regulation of gene expression. Recent data suggest that epigenetic abnormalities may occur very early in lung carcinogenesis. Systemic methylation changes may be a diagnostic marker for tumor development or prognosis. In this study, the expression and methylation of KMT2D and IGF2 genes were investigated in the lung cancer tissue compared to the adjacent normal tissue. Methods: The status of methylation of KMT2D and IGF2 genes were investigated in 30 patients with NSCLC after genomic DNA extraction using bisulfite treatment and MS-HRM method and the expression of these genes were checked by Real-Time PCR method in same samples. Results: For KMT2D gene, the expression and methylation level increased in 46.6% and 6.67% (respectively) for tumor samples comparison with normal samples (P>0.05). Also, for IGF2 gene 50% tumor samples overexpressed and 50% tumor samples showed that reduced expression comparison with the normal samples (P>0.05). In addition, 96.66% of tumor tissues did not show any change in methylation level for IGF2 gene promoter (P>0.05). Conclusion: This study showed that expression and methylation level of KMT2D and IGF2 genes did not change in NSCLC tumor samples compared to normal samples. However, this study was designed as a pilot study, and further investigations are required to confirm our findings.\u0000 Citation Format: Arash Matinahmadi, Zoofa Zayani, Seyed Hesamoddin Bidooki, Alireza Tavakolpournegari. Assessing gene expression and methylation of KMT2D and IGF2 genes in patients with non-small cell lung cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr B029.","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141363603","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":"Abstract PR006: DNA repair inhibition via targeting ATR activates cGAS/STING signaling, promotes anti-tumor immunity, and is a synthetic lethal strategy to augment immunotherapy response in preclinical models and clinical samples of small cell lung cancer","authors":"Triparna Sen","doi":"10.1158/1538-8514.synthleth24-pr006","DOIUrl":"https://doi.org/10.1158/1538-8514.synthleth24-pr006","url":null,"abstract":"\u0000 Introduction: Small cell lung cancer (SCLC) is the most aggressive subtype of lung cancer. Clinical trials of immune checkpoint blockade (ICB) combined with chemotherapy delivered only very modest benefits. In this study, we investigated the effect of targeting ataxia telangiectasia and rad3-related (ATR), the primary activator of the replication stress response, in SCLC. Clinical samples from treatment naïve and treated SCLC patients were analyzed by single cell and bulk RNA sequencing to ascertain the intratumoral transcriptional heterogeneity and the surrounding tumor microenvironment (TME). Methods: In this study, we investigated the effect of ATR inhibition either alone or in combination with PD-L1 blockade in multiple immunocompetent mouse models of SCLC. The downstream effects of ATR inhibition were assessed by bulk RNA sequencing, and multicolor flow cytometry. The SCLC clinical samples from treatment naïve and patients treated were analyzed by single cell and bulk RNA sequencing. Results: In multiple immunocompetent SCLC mouse models, ATR inhibition (ATRi) remarkably enhanced the anti-tumor effect of PD-L1 blockade. We next tested the ATR inhibition either alone or in combination with PD-L1 in the second-line regimen for SCLC. We observed that ATR inhibition in combination with PD-L1 blockade significantly reduced tumor volume and prolonged survival of aggressive mice models when compared to PD-L1 alone. Targeting ATR enhanced the expression of PD-L1, activated the cGAS/STING pathway, induced the expression of Type I and II interferon pathways, and caused significant infiltration of cytotoxic and memory/effector T-cells into tumors. Interestingly, ATRi also led to significant induction of MHC class I in SCLC in vitro and in vivo models. Single-cell RNA sequencing data provided a deep annotation of SCLC phenotypes and the surrounding immune TME. Treatment and subtype are associated with substantial phenotypic changes in the SCLC immune microenvironment, with greater T-cell dysfunction in SCLC-N than in SCLC-A. Moreover, a recurrent highly metastatic SCLC subset is associated with exhausted CD8+ T-cells and a pro-fibrotic, immunosuppressive monocyte/macrophage population, suggesting possible tumor-immune coordination to promote metastasis. Specifically, analysis of pre-and post-treatment clinical samples from a proof-of-concept study of a first-in-class ATR inhibitor, VX970 (berzosertib), and topotecan, in patients with relapsed SCLCs, validated the induction of MHC class I and interferon pathway genes, for the first time in this disease. Conclusion: We provide insight into tumor and immune biology in SCLC at single-cell resolution. Further, we show ATRi as a potentially transformative vulnerability of SCLC. Given the increasing importance of immunotherapy for the management of SCLC and that ATR inhibitors are already in clinical trials, combining ATR inhibitors with PD-L1-blockade offers an attractive strategy for the treatment of SCLC ","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141363447","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":"Abstract B010: Drug tolerant persister cancer cells escape therapy-induced senescence","authors":"Anne-Marie Fortier, Jason Topolski, Gabriel Alzial, A. Monast, H. Kuasne, D. Zuo, Alain Pacis, Genevieve Deblois, Morag Park","doi":"10.1158/1538-8514.synthleth24-b010","DOIUrl":"https://doi.org/10.1158/1538-8514.synthleth24-b010","url":null,"abstract":"\u0000 Triple-negative breast cancer (TNBC) accounts for 15% of breast cancers and is the most aggressive subtype lacking precision oncology therapeutic strategies. Standard-of-care is predominantly chemotherapy in the neoadjuvant setting (NACT). Despite good responses, ∼40% of TNBC patients develop resistance and present residual disease at surgery. Overcoming resistance and implementing better therapeutic options is critical. Our objectives are to develop targeting opportunities for drug tolerant persister (DTP) cells which underlie residual disease. Using our unique biobank of patient derived xenografts from treatment naive as well as NACT resistant TNBC, we developed longitudinal in vivo models of residual and relapse tumors to standard-of-care therapy. Transcriptomic analysis revealed transient metabolic changes such as oxidative phosphorylation, starvation and autophagy, associated with hallmarks of senescence at residual disease. We demonstrated that therapy-induced senescent cells in vitro can escape cell cycle arrest and resume proliferation through autophagy. Interfering with autophagy impairs redox balance, promotes ferroptosis and delays tumor relapse. These results support that autophagy is a promising targetable vulnerability in TNBC residual disease.\u0000 Citation Format: Anne-Marie Fortier, Jason Topolski, Gabriel Alzial, Anie Monast, Hellen Kuasne, Dongmei Zuo, Alain Pacis, Genevieve Deblois, Morag Park. Drug tolerant persister cancer cells escape therapy-induced senescence [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr B010.","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141365107","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}