bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B018: MTA-cooperative PRMT5 inhibitors selectively modulate RNA splicing in MTAP-deleted cancer cells across histologies
Authors: Tonini Matthew R , Meier Samuel R , Liu Shangtao , Cottrell Kevin M , Maxwell John P , Andersen Jannik N , Huang Alan , Cimmino Luisa , Briggs Kimberly J 
Published: December 2023

Abstract
PRMT5 is a type II arginine methyltransferase that forms an active complex with methylosome protein 50 (MEP50) to catalyze the symmetric dimethylation (SDMA) of arginine residues in proteins that regulate biological roles including modulation of apoptosis, DNA damage response and RNA processing. Some of the best characterized PRMT5 substrates are SNRPB, SNRPD1 and SNRPD3, which are necessary for the formation of the spliceosome and therefore RNA splicing fidelity. The development of MTA-cooperative PRMT5 inhibitors, including the clinical stage inhibitors TNG908 and TNG462, have been shown in preclinical studies to selectively inhibit PRMT5 in MTAP-deleted cancer cells while sparing normal, MTAP-intact cells. Consistent with this selective, on-target mechanism, treatment with TNG908 in preclinical studies results in increased aberrant RNA splicing in MTAP-deleted cells relative to MTAP-intact cells. As MTAP loss occurs in 10-15% of all human cancer, the identification of a signature of alternative splicing events may report pharmacodynamic activity of PRMT5 inhibitors and potentially predict patient response. Similar splicing alterations caused by PRMT5 inhibition were identified in preclinical MTAP-deleted cancer models representing glioblastoma, non-small cell lung cancer, among others, suggesting the events are histology-agnostic. Additionally, titration of exogenous MTA, an endogenous inhibitor of PRMT5, recapitulated the observed splicing events in preclinical MTAP-proficient cells. Similar findings were observed utilizing a pharmacological inhibitor of MTAP suggesting that the identified alternative splicing events are dependent on accumulation of MTA. Collectively, these data suggest that a PRMT5-dependent RNA splicing signature can be developed to identify solid tumors that may best respond to MTA-cooperative PRMT5 inhibitors as well as monitor their pharmacodynamic activity.
Citation Format: Matthew R Tonini, Samuel R Meier, Shangtao Liu, Kevin M Cottrell, John P Maxwell, Jannik N Andersen, Alan Huang, Luisa Cimmino, Kimberly J Briggs. MTA-cooperative PRMT5 inhibitors selectively modulate RNA splicing in MTAP-deleted cancer cells across histologies [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B018.
Abstract B029: Targeting phosphodiesterase: A potential strategy to treat LKB1-mutant cancers
Authors: Rono Catherine , Tang Xiaohu (Mark) 
Published: December 2023

Abstract
Cancer heterogeneity poses numerous challenges to treatment, underscoring the need for personalized/targeted therapies that align with each patient's specific genetic and molecular disease profile. Metabolic deregulation, often correlating with oncogenic alterations, is commonly observed in cancers. Such deregulation frequently presents metabolic vulnerabilities within the cancer, which could potentially be exploited for targeted therapy. Liver Kinase B1 (LKB1), a protein known for its diverse roles in cellular metabolism and its critical function as a tumor suppressor, ranks as the third most frequently mutated gene in non-small cell lung cancer (NSCLC). LKB1 mutations are linked to accelerated tumor progression and invasion, resulting in adverse clinical outcomes. Our research uncovers a novel role for LKB1 in cyclic nucleotide metabolism, wherein it suppresses a set of phosphodiesterase (PDE) expressions. Specifically, LKB1 represses PDE3 via the activation of the downstream salt-inducible kinase. Our data demonstrate that PDE3 modulators can selectively eliminate LKB1-deficient tumor cells while leaving LKB1-wildtype cells unharmed. However, some LKB1-deficient cells develop resistance due to the loss of SLFN12, whose expression is required for PDE3 modulator-induced cell death. Interestingly, this resistance can be overcome by inducing SLFN12 expression, through either epigenetic inhibitors or cAMP inducers. These findings not only broaden our understanding of the role of LKB1 in metabolic regulation but also suggest a promising strategy for targeted therapy against LKB1-mutant cancers.
Citation Format: Catherine Rono, Xiaohu (Mark) Tang. Targeting phosphodiesterase: A potential strategy to treat LKB1-mutant cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B029.
Abstract B061: Sensitivity and resistance mechanisms of human cancer cell lines treated with PARP, POLθ, and ATR inhibitor combinations in 2D and 3D spheroid cell viability assays
Authors: Melis Janneke J.T.M. , Kooijman Jeffrey , Wetemans Sabine , Geerdink-Datema Suzan , Dylus Jelle , de Roos Jeroen A.D.M. , van Riel Wilhelmina E. , Zaman Guido J.R. 
Published: December 2023

Abstract
Poly ADP Ribose Polymerase (PARP) inhibitors have changed the landscape of treatment of homologous recombination (HR) -deficient cancers. The combination of PARP targeting agents and genetic alterations in the HR pathway is known to be synthetically lethal. Currently, four PARP inhibitors are approved for treatment of HR-deficient cancers. In combination with DNA damaging agents, PARP inhibitors synergistically kill tumor cells. Occurrence of resistance to PARP inhibitors is a major problem in the clinic. Targeting alternative DNA repair pathways or the use of new drug combinations may overcome PARP inhibitor resistance. We have determined and compared the effect of inhibitors of PARP, POLθ and ATR on cell viability in a large panel of human cancer cell lines (the Oncolines® panel) in 2D cell viability assays, using intracellular ATP content as an indirect read-out of cell number. The relationship between the mutation and expression status of genes involved in the DNA damage response pathway, or known to be involved in PARP inhibitor resistance, was determined. The effect of co-treatment of PARP inhibitors with inhibitors of POLθ, ATR and DNA damaging, cytotoxic agents was determined in BLISS combination matrix experiments in the colorectal adenocarcinoma cell line DLD1 and an isogenic BRCA2-deficient knock-out derivative. Drug combinations were studied in 2D and in 3D spheroid viability assays. To identify novel, potential mechanisms of resistance to PARP inhibitors, BRCA1-deficient ovarian UWB1.289 and BRCA2-deficient DLD1 cells were treated with sequentially increasing concentrations of PARP inhibitors talazoparib or olaparib. Resistant clones were selected and characterized. Our study reveals insight into the genetic determinants of cancer cell line sensitivity to inhibitors of PARP, POLθ and ATR. We also present the first side-by-side comparative study of the effect of drug combinations targeting the DNA damage response pathway in HR-deficient tumors in 2D and 3D spheroid cell viability assays.
Citation Format: Janneke J.T.M. Melis, Jeffrey Kooijman, Sabine Wetemans, Suzan Geerdink-Datema, Jelle Dylus, Jeroen A.D.M. de Roos, Wilhelmina E. van Riel, Guido J.R. Zaman. Sensitivity and resistance mechanisms of human cancer cell lines treated with PARP, POLθ, and ATR inhibitor combinations in 2D and 3D spheroid cell viability assays [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B061.
Abstract B062: Loss of MED12 activates the TGFβ pathway to promote chemoresistance and replication fork stability in BRCA-deficient cells
Authors: Pale Lindsey M , Dhoonmoon Ashna , Hale Anastasia , Dennis Kady A , Schleicher Emily M , Nicolae Claudia M , Moldovan George-Lucian 
Published: December 2023

Abstract
Understanding chemoresistance mechanisms in BRCA-deficient cells will allow for identification of biomarkers for predicting tumor response to therapy, as well as the design of novel therapeutic approaches targeting this chemoresistance. Here, we show that the protein MED12, a component of the Mediator transcription regulation complex, plays an unexpected role in regulating chemosensitivity in BRCA-deficient cells. We found that loss of MED12 confers resistance to cisplatin and PARP inhibitors in both BRCA1- and BRCA2-deficient cells, which is associated with restoration of both homologous recombination and replication fork stability. Surprisingly, MED12-controlled chemosensitivity does not involve a function of the Mediator complex, but instead reflects a distinct role of MED12 in suppression of the TGFβ pathway. Importantly, we show that ectopic activation of the TGFβ pathway is enough to overcome the fork protection and DNA repair defects of BRCA-mutant cells, resulting in chemoresistance. Our work identifies the MED12-TGFβ module as an important regulator of genomic stability and chemosensitivity in BRCA-deficient cells.
Citation Format: Lindsey M Pale, Ashna Dhoonmoon, Anastasia Hale, Kady A Dennis, Emily M Schleicher, Claudia M Nicolae, George-Lucian Moldovan. Loss of MED12 activates the TGFβ pathway to promote chemoresistance and replication fork stability in BRCA-deficient cells [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B062.
Abstract B068: Modulation of the DNA damage response by novel Ku-DNA binding inhibitors enhances cellular effects of DNA-double strand break inducing agents
Authors: Mendoza-Munoz Pamela L , Chauhan Dineshsinha , Gavande Navnath S , Turchi John J 
Published: December 2023

Abstract
The DNA-dependent protein kinase (DNA-PK) plays a critical role in the non-homologous end joining (NHEJ) double-strand break (DSB) repair pathway and the DNA damage response (DDR). Consequently, blocking DNA-PK kinase activity is being pursued as a therapeutic strategy for the treatment of cancer in combination with DNA-double strand break inducing agents. We have previously reported the development of Ku-DNA binding inhibitors (Ku-DBi’s) that act via a novel mechanism of action to inhibit DNA-PK catalytic kinase activity by targeting the Ku 70/80 heterodimer interaction with DNA. Ku-DBi’s display nanomolar activity in vitro, possess cellular DNA-PK and NHEJ inhibitory activity, and sensitize non-small cell lung cancer (NSCLC) cells to DSB generating therapies bleomycin, etoposide and ionizing radiation. In this study, we have expanded our structure activity relationship analyses to focus on optimizing cellular uptake and reducing protein binding. We present the synthesis and analysis of a new series of Ku-DBi’s which demonstrated that chemical modifications of the X80 core structure can be implemented to achieve these goals while retaining Ku inhibitory activity. Furthermore, novel relationships with in vitro inhibitory activity were identified as a function of new pharmacophore additions. In addition, these novel compounds display reduced non-specific protein binding, increased cellular uptake, and enhanced cellular inhibition on DNA-double strand break repair. These novel compounds enable cellular studies to be conducted in serum contain media and the pursuit of in vivo analysis and represent a significant advance in the development of Ku-DNA binding inhibitors.
Citation Format: Pamela L Mendoza-Munoz, Dineshsinha Chauhan, Navnath S Gavande, John J Turchi. Modulation of the DNA damage response by novel Ku-DNA binding inhibitors enhances cellular effects of DNA-double strand break inducing agents [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B068.
Abstract B080: Non-genetic determinants driving sub-clonal resistance to KRAS G12C combination therapies in KRAS mutant non-small cell lung cancer
Authors: Li Chendi , Graser Christopher J , Qin Qian , Syed Usman M , Karakyriakou Barbara , Clark Sarah E , Saiki Anne Y , Hughes Paul E , Ott Christopher , Pinello Luca , Michor Franziska , Hata Aaron N 
Published: December 2023

Abstract
The FDA approval of the KRAS G12C inhibitor (G12Ci) sotorasib and the advancement of similar drugs into the clinic marks a major milestone in treating KRAS G12C non-small cell lung cancer (NSCLC). However, not all patients respond (sotorasib – ORR = 37.1%, adagrasib - 43%, JDQ443 – 35%), motivating preclinical and clinical investigation into mechanisms of intrinsic and acquired resistance. For instance, clinical studies have reported on-target KRAS mutations and preclinical studies have demonstrated mitogen-activated protein kinase (MAPK) feedback reactivation including EGFR, SHP2, and WT RAS signaling. In response to targeted therapies, sub-populations of cells can enter quiescence or specific epigenetic-driven states that confer drug tolerance. However, epigenetic states defining drug-tolerant persister populations and contributing to adaptive resistance to KRAS G12Ci have not been reported. Using a high-complexity DNA-barcoding system and mathematical modeling, we observed that pre-existing resistant clones to KRAS G12Ci gain clonal fitness during treatment independent of growth rate. Using single-cell profiling and RNA-lineage tracing barcoded systems, we identified distinct subpopulations of cells defined by specific chromatin and transcriptional states, including activation of interferon-gamma genes (ISG) and increased chromatin accessibility for pioneer transcription factors, which may contribute to MAPK reactivation-driven resistance. These results suggest a potential role of pioneer transcription factor-activated interferon-gamma response in driving MAPK feedback reactivation in KRAS G12Ci- resistant tumor subpopulations.
Citation Format: Chendi Li, Christopher J Graser, Qian Qin, Usman M Syed, Barbara Karakyriakou, Sarah E Clark, Anne Y Saiki, Paul E Hughes, Christopher Ott, Luca Pinello, Franziska Michor, Aaron N Hata. Non-genetic determinants driving sub-clonal resistance to KRAS G12C combination therapies in KRAS mutant non-small cell lung cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B080.
Abstract B105: Antineoplastic effects and expression modulations in proliferation/apoptosis related genes by riproximin in breast cancer cells
Authors: Pervaiz Asim , Khan Asma , Umer Kiran , Berger Martin R. 
Published: December 2023

Abstract
Background: Ribosomal inactivating proteins (RIPs) target the ribosomal machinery of target cells and stop the translational machinery irreversibly. Riproximin is a plant-based RIP which was extracted and purified from the plant “Ximenia americana”. Riproximin has demonstrated its anticancer effects against various in vitro and in vivo cancer models. In this study, the focus was to evaluate the effects of riproximin on proliferation and apoptosis of breast cancer cells at functional and molecular levels.
Methods: MTT dye reduction assay and DAPI nuclear staining methodologies were used to highlight the riproximin mediated effects on proliferation and apoptosis in primary (MCF-7) and metastatic (MDA-MB-231) breast cancer cell lines. Afterwards, the two cell lines were used to investigate the expression modulations in genes related to PIK3/Akt and apoptosis pathways (84 genes/pathway) via real-time PCR methodology. The expression modulations were used to build the signalling pathways via Ingenuity Pathway Analysis supported by Qiagen software system.
Results: Riproximin successfully halted the proliferation of the breast cancer cells with an average 50% inhibitory concentrations of 1.2 and 2.9 ng/ml after 72 hours exposure interval in MCF-7 and MDA-MB-231 cells, respectively. The protein also induced apoptotic effects in the two cell lines as reflected by shrinkage, blebbing and fragmentation of the nucleus/DNA content in a concentration dependant format. Substantial alterations (≥2fold) were observed in PIK3/Akt pathway genes (MCF-7: 49/84, MDA-MB-231: 28/84) in response to riproximin exposure. Similarly, the protein induced de-regulation (≥2fold) of apoptosis related 44/84 and 34/84 genes in MCF-7 and MDA-MB-231 cell lines, respectively. The Ingenuity Pathway Analysis revealed involvement of these genes at distinct positions in cell survival and death mechanisms.
Conclusion: Riproximin demonstrated the substantial potential to induce the cytotoxic effects in breast cancer cells. The protein also de-regulated a significant number of proliferation and apoptosis related genes in breast cancer primary and metastatic cells. Further in vitro investigations are required to understand the fine molecular tuning being operated by this natural plant protein in cancer cells.
Citation Format: Asim Pervaiz, Asma Khan, Kiran Umer, Martin R. Berger. Antineoplastic effects and expression modulations in proliferation/apoptosis related genes by riproximin in breast cancer cells [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B105.
Abstract C010: A comprehensive predictive biomarker analysis for MEK Inhibitors in Patient-derived Xenograft (PDX) models
Authors: Sheng Yanghui , Qian Wubin , Wang Jingjing , Guo Sheng 
Published: December 2023

Abstract
Introduction: The RAS-RAF-MEK-ERK pathway has been extensively studied for its prominent role in cancer development. Activating mutations in receptor tyrosine kinases, RAS, or RAF, are commonly observed in cancer. Pathway activation caused by these mutations is mediated through MEK kinases, making MEK inhibition an attractive therapeutic strategy. Although several in vitro studies have been carried out to identify predictive biomarkers for sensitivity to MEK inhibition, the results have not been validated in vivo.
Methods: Cryopreserved or fresh PDX tumor tissues (~2–3 mm in diameter) were transplanted into NOD/SCID or BALB/c nude mice subcutaneously. Trametinib was administered orally daily at 0.3mg - 1mg/kg of body weight, starting when tumor size reached 100-300 mm3. Sequencing reads were aligned to both human and mouse reference genomes. Based on which alignment yielded fewer mismatches, they were subsequently sorted into human or mouse groups, representing cancer and stromal transcriptomes, respectively. Ambiguous readings were discarded. Transcript abundance was quantified using the Kallisto software tool. Nucleotide variants in human genes were detected using the GATK best practice workflow.
Results: We systematically analyzed tumor growth data collected from 62 PDX models in 9 cancer types (colorectal, head and neck, esophageal, kidney, melanoma, lung, gastric, ovarian, and pancreatic) treated with Trametinib, an allosteric MEK1/2 inhibitor. The responses to Trametinib were classified into 3 categories based on the amount of tumor growth inhibition (TGI) achieved. About 20% of these models were sensitive to Trametinib treatment (TGI &gt; 70% compared to vehicle), 35% were resistant (TGI ≤ 30% compared to vehicle), and the remaining showed a partial response (30% &lt; TGI ≤ 70% compared to vehicle). Cross-group comparisons of PDX transcriptomic and mutation profiles allowed identification of novel biomarkers as well as validation of biomarkers previously reported in in vitro studies.
Conclusions: The different sensitivity to MEK inhibition observed in PDX models mirrors the patient heterogeneity observed in clinic. Thus, our results highlight the need to identify the appropriate genetic background using predictive biomarkers when applying targeted therapies.
Citation Format: Yanghui Sheng, Wubin Qian, Jingjing Wang, Sheng Guo. A comprehensive predictive biomarker analysis for MEK Inhibitors in Patient-derived Xenograft (PDX) models [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C010.
Abstract C042: Integrative analyses of CRISPR and drug screens identify a selective and potent compound for oral squamous cell carcinoma
Authors: Chai Annie Wai Yeeng , Tan Yee Hua , Ooi Shiyin , Yee Pei San , Yee Shi Mun , Lightfoot Howard , Bathorpe Syd , Garnett Mathew J , Cheong Sok Ching 
Published: December 2023

Abstract
Mechanism-guided drug repurposing can accelerate the development of therapeutic strategies for oral squamous cell carcinoma (OSCC), which has an unmet clinical need. We integrated cell line sensitivity data for 339 anti-cancer drugs with genome-wide CRISPR-Cas9 screen gene essentiality data for 21 unique OSCC cell lines, derived primarily from Asian patients. We identified a significant correlation between AZD5582 sensitivity (an antagonist of the inhibitor of apoptosis (IAP) family proteins), and dependency on several members of the NF kappa-B pathway (RNF31, MAP3K7 and IKBKG). Dependent OSCC lines are more sensitive to AZD5582, with nanomolar range half-maximal inhibitory drug concentrations (IC50). We confirmed the on-target specificity and potency of AZD5582 in vitro and in vivo. Furthermore, AZD5582 sensitivity was associated with high levels of tumor necrosis factor (TNF) and either functional apoptotic or necroptotic pathways. In summary, our approach of integrating pharmacological and CRISPR screen data in a unique cohort of OSCC cell lines data has enabled the identification of specific dependencies and drug repurposing candidates.
Citation Format: Annie Wai Yeeng Chai, Yee Hua Tan, Shiyin Ooi, Pei San Yee, Shi Mun Yee, Howard Lightfoot, Syd Bathorpe, Mathew J Garnett, Sok Ching Cheong. Integrative analyses of CRISPR and drug screens identify a selective and potent compound for oral squamous cell carcinoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C042.