bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B017: Loss of UXS1 selectively kills KEAP1 mutant cancer cell lines by depleting pyrimidines and inducing replication stress
Authors: Hoffman Timothy , Gebru Melat , Boudreau Aaron , Han Fei , Foster-Duke Kelly , Gajda Jessica , Vu Ngoc , Bennett Bryson , Kort Michael , Shotwell Brad , Hickson Jonathan , Wilsomn Noel , Stokoe David 
Published: June 2024

Abstract
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.
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.
Abstract B018: Investigating vulnerabilities associated with chromosome arm aneuploidy in cancer
Authors: Zhakula-Kostadinova Nadja , Jain Sejal , Byron Laura , Meyerson Matthew L. , Taylor Alison M. 
Published: June 2024

Abstract
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.
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.
Abstract B026: Screening non-small cell lung cancer patient-derived organoids with epigenetic probes reveals PRMT5 as an oncogenic target
Authors: Jafarova Khadija , Li Quan , Radulovich Nikolina , Liu Geoffrey , Tsao Ming S 
Published: June 2024

Abstract
Lung cancer is the leading cause of cancer-related mortality. Detection of drug actionable genetic alterations has made the standard systemic therapy to a more personalized one including targeted therapy and immune checkpoint blockade. Despite the initial response, majority of patients develop resistance to treatment. Therefore, understanding the mechanisms of resistance as well as discovering novel cancer targets is necessary. Resistance to therapies can be associated with an existing clone of tumor cells with genetic alteration, or the emergence of cells with epigenetic changes overcoming the treatment-induced stress. Therefore, investigating the epigenetic aberrations that occur in tumor cells may reveal novel targetable markers that can be of great clinical significance. Methods: Organoid models established from non-small cell lung cancer (NSCLC) patient surgical resections and pleural effusion were dissociated into single cells and plated in matrigel-coated 384-well plate. A panel of 32 NSCLC organoid models were treated with a library of 41 epigenetic probes (1uM) and a DMSO control over a period of 8 days. Cell titre glo assay was performed to measure cell survival. Results: Arginine methyl transferase protein 5 (PRMT5) inhibited the cell growth of large proportion of the NSCLC organoid models. LLY-283 showed the most significant effect, with 50% of all organoid models (16/32) treated with LLY283 showing ≥50% reduction in cell viability. Further testing with multiple concentrations of several PRMT5 inhibitors revealed models with differential responses to PRMT5 inhibition. To investigate the differential gene expression changes induced by PRMT5 inhibition, we performed RNA-sequencing on three PRMT5 inhibitor sensitive and three resistant organoid models. Ongoing analyses aim at identifying differentially expressed genes in sensitive and resistant models in response to PRMT5 inhibition, and pathway enrichment analysis to determine the differential mechanisms of response to PRMT5 inhibition. Conclusion: Epigenetic drug screening on a large cohort of NSCLC organoid models reveals PRMT5 as potential novel therapeutic target in NSCLC. Further correlative analysis with transcriptomic changes induced by the PRMT5 inhibitors may reveal biomarkers of response.
Citation Format: Khadija Jafarova, Quan Li, Nikolina Radulovich, Geoffrey Liu, Ming S Tsao. Screening non-small cell lung cancer patient-derived organoids with epigenetic probes reveals PRMT5 as an oncogenic target [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 B026.
Abstract B029: Assessing gene expression and methylation of KMT2D and IGF2 genes in patients with non-small cell lung cancer
Authors: Matinahmadi Arash , Zayani Zoofa , Bidooki Seyed Hesamoddin , Tavakolpournegari Alireza 
Published: June 2024

Abstract
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&gt;0.05). Also, for IGF2 gene 50% tumor samples overexpressed and 50% tumor samples showed that reduced expression comparison with the normal samples (P&gt;0.05). In addition, 96.66% of tumor tissues did not show any change in methylation level for IGF2 gene promoter (P&gt;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.
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.
Abstract IA011: Towards mapping the landscape of cancer vulnerabilities
Authors: Vazquez Francisca 
Published: June 2024

Abstract
I will introduce the Cancer Dependency Map (DepMap) project. This project aims to build a resource to identify the landscape of cancer vulnerabilities by linking molecular alterations of tumors to gene dependencies or drug sensitivities. This resource is being used by scientists around the world and has made significant contributions to basic and translational cancer research. I will describe how we are building DepMap and the multiple components it requires. Additionally, I will discuss ongoing projects to expand DepMap, including screening next-generation models. I will also present how to identify potential therapeutic targets using DepMap data and the emerging types of targets. Lastly, I will highlight a recently identified synthetic lethal target in the ribosome rescue pathway in molecularly defined patient populations, demonstrating the power of DepMap in identifying such targets.
Citation Format: Francisca Vazquez. Towards mapping the landscape of cancer vulnerabilities [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 IA011.
Abstract IA018: Vulnerabilities of TP53-mutated AML and therapeutic implications
Authors: Bhatt Shruti 
Published: June 2024

Abstract
Acute myeloid leukemia (AML) is a complex and genetically diverse with an overall survival rate of less than 32%. Despite the remarkable success of targeted therapy in mediating remission, the emergence of acquired resistance remains a major clinical challenge to overcome. The prevailing understanding of acquired resistance identifies successive genetic changes as the primary cause.TP53 mutations are found in 70-80% of acute myeloid leukemia (AML) patients with complex karyotypes and associated with resistance towards both conventional chemotherapy and newly approved venetoclax plus azacytidine (VEN/AZA) combination. By using CRISPR-Cas9-edited isogenic AML cells harboring, mutation (6 missense mutations) or deletion (KO) of TP53, we found that TP53 mutant/KO cells are less sensitive to etoposide or VEN-AZA induced apoptosis compared to WT without defect in G1 arrest. Surprisingly, we found that TP53-mutant and TP53-wild-type (WT) isogenic AML cells and primary tumors (n=40) had comparable mitochondrial outer membrane permeabilization (MOMP) at baseline, despite the key role of TP53 in transcriptionally activating proapoptotic regulators of MOMP (such as BAX, PUMA, and NOXA). Based on these findings, we hypothesize that the targets downstream of mitochondrial permeabilization drive resistance to HMA/VEN combinations in TP53 mutant disease. By leveraging unbiased bulk RNA-seq and proteomics, and whole genome CRISPR-cas9 screen we identified IAPs as functional vulnerability. Collectively we reveal novel chemoresistance mechanisms in TP53 mutant/KO downstream of MOMP and provide a targeting strategy to improve existing therapy by targeting non-transcriptional function of TP53 in overcoming therapy resistance.
Citation Format: Shruti Bhatt. Vulnerabilities of TP53-mutated AML and therapeutic implications [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 IA018.
Abstract IA019: Identification of metabolic adaptation mechanisms that confer resistance to glutathione depletion in Ewing sarcoma
Authors: Sorensen Poul H. , Zhang Hai-Feng , Hughes Christopher , Delaidelli Alberto , Aparicio Samuel 
Published: June 2024

Abstract
Aggressive cancer cells must overcome diverse stress forms in the tumor microenvironment and circulation, such as oxidative stress, to survive and metastasize. One adaptive process to counter oxidative stress is to upregulate glutathione (GSH), a tripeptide consisting of glutamate, cysteine, and glycine, which is a powerful antioxidant in cells, including in tumor cells. A rate-liming step in GSH production is the availability of the amino acid, cysteine. Tumor cells can either import cystine, a dimer of cysteine, through the xCT antiporter system, for conversion to the reduced cysteine monomer, or in some tumor types, they can synthesize cysteine de novo from methionine and serine through the transsulfuration pathway. GSH is not only critical for redox homeostasis, but is taken up into mitochondria where is acts as a source of sulphur to generate iron-sulphur (Fe-S) clusters that are essential for many mitochondrial enzymes including electron transport complexes. We wished to determine if Ewing sarcoma cells could tolerate reduced levels of GSH, using either xCT genetic or pharmacologic inhibition, or by blocking downstream enzymes in the GSH synthesis pathway, including GCLC using buthionine sulfoximine (BSO), or glutaminase using CB-839. To our surprise, we were able to generate BSO and CB-839 resistant cells with vanishingly low levels of GSH. These cells somehow maintained not only redox homeostasis, but also showed functional mitochondrial respiration (oxidative phosphorylation). We then performed CRISPR dropout screens to identify how these cells might be surviving in the absence of GSH, and to tease out specific dependencies of these BSO and CB-839 resistant cells. These studies revealed unexpected dependencies, and opportunities for synthetic lethal interventions, as will be discussed.
Citation Format: Poul H. Sorensen, Hai-Feng Zhang, Christopher Hughes, Alberto Delaidelli, Samuel Aparicio. Identification of metabolic adaptation mechanisms that confer resistance to glutathione depletion in Ewing sarcoma [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 IA019.
Abstract IA022: Mechanisms of splicing dysregulation and dependency in cancer
Authors: Karlin Kristen 
Published: June 2024

Abstract
Dysregulated RNA splicing is a hallmark feature of cancer. Much like mutational signatures in tumors, RNA mis-splicing patterns are widely heterogeneous and segregate tumors into clades, suggesting there are distinct mechanisms underlying these splicing aberrations. However, the mechanisms driving such distinct RNA splicing dysregulation remain largely unknown. Herein, we discovered that copy-number variation of essential splicing factors is a pervasive cause of splicing dysregulation, and in some tumor contexts, confers deep dependencies on RNA-binding proteins (RBPs) that converge on these mechanisms. Using a systematic chemical biology approach, we delineate how splicing RBPs participate in distinct types of RNA quality control in cells, and when disrupted, produce surprisingly unique patterns of RNA mis-splicing. These RBP-specific mis-splicing patters are common in distinct cancer types. Notably, unbiased genome-wide analysis revealed that RBP-specific mis-splicing patterns found in tumors were significantly associated with copy number loss of a network of functionally linked splicing factors. These splicing factors often reside on tumor suppressor loci that are frequently deleted in breast and other cancers, suggesting that copy number loss of essential splicing RBPs is a collateral event with selected loss of tumor suppressors. Importantly, RBP-specific mis-splicing signatures also segregate tumor models that are dependent on the concordant RBP, suggesting that these tumors evolve defects in RBP function that predispose them to further perturbation. Together, our work suggests that deletions of tumor suppressor loci may drive collateral dysregulation of RNA splicing through partial loss of splicing RBPs and provokes the hypothesis that these mis-splicing signatures may predict actionable dependencies in the cancers that harbor them.
Citation Format: Kristen Karlin. Mechanisms of splicing dysregulation and dependency 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 IA022.
Abstract IA023: Targeting epigenetic complexes in leukemia
Authors: Grembecka Jolanta 
Published: June 2024

Abstract
Chromatin-associated multi-protein complexes, which often comprise proteins involved in epigenetic regulation, play an important role in various cancers, including leukemia. Thus, pharmacologic inhibition of proteins involved in these complexes can lead to new anti-cancer therapies. We have focused on therapeutic targeting of various chromatin-bound multi-protein complexes, including Mixed Lineage Leukemia 1 (MLL1) and Polycomb Repressive Complex 1 (PRC1) complexes, as a novel treatment for leukemia. These efforts led to the development of small molecule inhibitors targeting the menin-MLL1 interaction, which were translated to leukemia patients, demonstrating promising efficacy in Acute Myeloid Leukemia (AML) with NPM1 mutations or MLL1 translocations. However, clinical studies revealed resistance to the single agent menin inhibitor in a sub-set of AML patients, suggesting that combinatorial treatments or new generations of menin inhibitors might be required to overcome resistance. Our recent efforts to address resistance to menin inhibitors will be presented, including combinatorial studies with other targeted agents (e.g. kinases inhibitors), which resulted in synergistic effects. Furthermore, discovery of a new generation of menin inhibitors with promising activity against menin patient mutations will also be presented.
Citation Format: Jolanta Grembecka. Targeting epigenetic complexes in leukemia [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 IA023.
Arithmetic in two languages: Localizing simple multiplication processing in the adult bilingual brain
Authors: Cerda Vanessa R. , Suárez-Pellicioni Macarena , Booth James R. , Wicha Nicole Y. 
Published: June 2024

Abstract
Verbally memorized multiplication tables are thought to create language-specific memories. Supporting this idea, bilinguals are typically faster and more accurate in the language in which they learned math (LA+) than in their other language (LA-). No study has yet revealed the underlying neurocognitive mechanisms explaining this effect, or the role of problem size in explaining the recruitment of different brain regions in LA+ and LA-. To fill this gap in the literature, 29 Spanish-English early bilingual adults, proficient in both languages, verified simple multiplication problems in each language while functional magnetic resonance imaging (fMRI) was acquired. More specifically, this study aimed to answer two questions: 1) Does LA+ recruit left superior and middle temporal gyri (STG/MTG) to a greater extent than LA-, reflecting more robust verbal representations of multiplication facts in LA+? In contrast, does LA- recruit the inferior frontal gyrus (IFG), reflecting more effortful retrieval, or the intraparietal sulcus (IPS), reflecting reliance on quantity processes? 2) Is there an interaction between language and problem size, where language differences are more pronounced for less practiced, large multiplication problems (e.g., 8 x 9) in comparison to more familiar, small problems (e.g., 2 x 3). Functional localizer tasks were used to identify hypothesis-driven regions of interest in verbal areas associated with verbal representations of arithmetic facts (left STG/MTG) and with the effortful retrieval of these facts (left IFG) and quantity areas engaged when calculation-based strategies are used (bilateral IPS). In planned analyses, no cluster reached significance for the direct comparison of languages (question 1) or for the interaction between language and problem size (question 2). An exploratory analysis found a main effect of problem size, where small problems recruited left STG/MTG and left IFG to a greater extent than large problems, suggesting greater verbal involvement for these problems in both languages. Additionally, large problems recruited right IPS to a greater extent than small problems, suggesting reliance on quantity processes. Our results suggest that proficient early bilingual adults engage similar brain regions in both languages, even for more difficult, large problems.
PE/PPE mutations in the transmission of Mycobacterium tuberculosis in China revealed by whole genome sequencing
Authors: Fang Wei-wei , Kong Xiang-long , Yang Jie-yu , Tao Ning-ning , Li Ya-meng , Wang Ting-ting , Li Ying-Ying , Han Qi-lin , Zhang Yu-zhen , Hu Jin-jiang , Li Huai-chen , Liu Yao 
Published: June 2024

Abstract
Objective
This study aims to examine the impact of PE/PPE gene mutations on the transmission of Mycobacterium tuberculosis (M. tuberculosis) in China.

Methods
We collected the whole genome sequencing (WGS) data of 3202 M. tuberculosis isolates in China from 2007 to 2018 and investigated the clustering of strains from different lineages. To evaluate the potential role of PE/PPE gene mutations in the dissemination of the pathogen, we employed homoplastic analysis to detect homoplastic single nucleotide polymorphisms (SNPs) within these gene regions. Subsequently, logistic regression analysis was conducted to analyze the statistical association.

Results
Based on nationwide M. tuberculosis WGS data, it has been observed that the majority of the M. tuberculosis burden in China is caused by lineage 2 strains, followed by lineage 4. Lineage 2 exhibited a higher number of transmission clusters, totaling 446 clusters, of which 77 were cross-regional clusters. Conversely, there were only 52 transmission clusters in lineage 4, of which 9 were cross-regional clusters. In the analysis of lineage 2 isolates, regression results showed that 4 specific gene mutations, PE4 (position 190,394; c.46G > A), PE_PGRS10 (839,194; c.744 A > G), PE16 (1,607,005; c.620T > G) and PE_PGRS44 (2,921,883; c.333 C > A), were significantly associated with the transmission of M. tuberculosis. Mutations of PE_PGRS10 (839,334; c.884 A > G), PE_PGRS11 (847,613; c.1455G > C), PE_PGRS47 (3,054,724; c.811 A > G) and PPE66 (4,189,930; c.303G > C) exhibited significant associations with the cross-regional clusters. A total of 13 mutation positions showed a positive correlation with clustering size, indicating a positive association. For lineage 4 strains, no mutations were found to enhance transmission, but 2 mutation sites were identified as risk factors for cross-regional clusters. These included PE_PGRS4 (338,100; c.974 A > G) and PPE13 (976,897; c.1307 A > C).

Conclusion
Our results indicate that some PE/PPE gene mutations can increase the risk of M. tuberculosis transmission, which might provide a basis for controlling the spread of tuberculosis.