bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B083: Secondary KRAS mutations lead to acquired resistance to KRASG12D inhibitor in colorectal cancer
Authors: Lieb Simone , Jurado Sabine , Nowoshilow Sergej , Zak Krzysztof M. , Hofmann Marco H. 
Published: December 2023

Abstract
KRAS is the most frequently mutated oncogene, with high prevalence in tumor types with a significant unmet clinical need, such as colorectal cancer (CRC). Activating mutations in the KRAS gene leading to amino acid exchange at position 12 from Glycine to Asparagine, G12D, occur in approximately 12.5% of CRC. The approval of mutant specific KRASG12C inhibitors MRTX849 and AMG510 by the FDA raised the question if KRAS targeted therapy approaches could provide benefit to cancer patients with other mutant alleles. Several KRASG12D inhibitors have recently been described and MRTX1133, a selective KRASG12D inhibitor from Mirati Therapeutics, has now entered clinical trial, recruiting patients with advanced solid tumors harboring a KRAS G12D mutation. Alongside the great hopes placed in KRAS targeting therapy, resistance is likely to occur, as it was observed in patients relapsing in response to KRASG12C inhibitors. We aimed to use this pre-clinical study to predict and understand potential resistance mechanisms that may arise during targeted treatment against KRASG12D in the CRC setting. To this aim, the colorectal cancer cell line GP2d was continuously treated with MRTX1133 to generate resistance and individual outgrowing clones were subsequently profiled in a series of assays to identify potential mechanism(s). These assays included analysis of gene expression changes, mutation calling, as well as qPCR and protein-based assays. Interestingly, we identified two individual secondary on-target mutations in the KRAS gene, which could affect binding of MRTX1133 to the pocket in KRAS. These findings were confirmed in an orthogonal assay, by screening for resistance in Ba/F3 cells transduced with the corresponding KRAS double mutant. Combination assays were then performed in parental and resistant cells to study whether additional vertical or alternative pathway inhibition could address the resistance. Collectively our pre-clinical study identified secondary KRAS mutations in the compound binding pocket as a mechanism of resistance to KRAS G12D inhibition by MRTX1133 in colorectal cancer cells.
Citation Format: Simone Lieb, Sabine Jurado, Sergej Nowoshilow, Krzysztof M. Zak, Marco H. Hofmann. Secondary KRAS mutations lead to acquired resistance to KRASG12D inhibitor in colorectal 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 B083.
Abstract B088: VT3989, the first-in-class and first-in-human TEAD auto-palmitoylation inhibitor, enhances the efficacy and durability of multiple targeted therapies of the MAPK and P13K/AKT/mTOR pathways
Authors: Tang Tracy T , Post Leonard 
Published: December 2023

Abstract
TEAD transcription factors are the major effectors of the Hippo-YAP/TAZ-TEAD pathway involved in the regulation of cell proliferation, survival, and cell migration. TEAD auto-palmitoylation has been shown to be required for TEAD interaction with coactivator YAP/TAZ and hence activation of transcriptional activity. There are multiple reports that YAP/TEAD activation provides the essential survival signal in drug-tolerant persister/dormant cells in cancer in response to treatment with targeted therapies, leading to drug resistance and cancer relapse in BRAF-mutant, KRAS-mutant, EGFR-mutant, and ALK-rearranged non–small cell lung cancers (NSCLC). The TEAD inhibitor VT3989, currently in clinical testing, was evaluated for effect on emerging drug tolerant persister/dominant cancer cells and drug resistance. VT3989, with similar biological activity in vitro and in vivo as the potent small molecule TEAD auto-palmitoylation inhibitors reported (Tang et al, 2021, Mol Cancer Ther. 20(6):986-998), disrupts YAP/TAZ-TEAD protein interaction, suppresses TEAD transcriptional activity, and selectively blocks proliferation of NF2-deficient mesothelioma in vitro and inhibit NF2 mutant xenograft tumor growth in vivo. In in vitro assays as well as in vivo studies using cell line derived (CDX) and patient derived (PDX) xenograft models, VT3989 enhanced the efficacy and durability of clinically approved EGFR inhibitors (osimertinib, lazertinib), MET inhibitors (savolitinib, capmatinib), EGFR-MET bispecific antibody (amivantinib), KRAS-G12C inhibitors (sotorasib, adagrasib), BRAF inhibitors (encorafenib, dabrafenib), MEK inhibitors (trametinib, cobimetinib), and mTORC inhibitor (everolimus). With the addition of VT3989, combination anti-tumor effect was observed and/or tumor regrowth was delayed compared to monotherapy alone. Therefore, in addition to Hippo-YAP/TAZ-TEAD pathway driven cancers, such as mesothelioma, where VT3989 can show monotherapy efficacy, future VT3989 clinical studies will include combination therapy with approved targeted therapies to enhance the efficacy and durability of treatment.
Citation Format: Tracy T Tang, Leonard Post. VT3989, the first-in-class and first-in-human TEAD auto-palmitoylation inhibitor, enhances the efficacy and durability of multiple targeted therapies of the MAPK and P13K/AKT/mTOR pathways [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 B088.
Abstract B098: Unbiased in vitro and in vivo drug anchor screens identify mechanisms of resistance and sensitization for MTA-cooperative PRMT5 inhibitors in MTAP-deleted cancer models
Authors: Lombardo Steven , Tonini Matthew R , Grove Lauren , Fenoglio Silvia , Tepper James , Shen Binzhang , Stowe Hannah , Liu Shangtao , Meier Samuel R , Choi Ashley H , Khendu Tenzing , Yu Yi , Cottrell Kevin M , Maxwell John P , Andersen Jannik N , Huang Alan , Briggs Kimberly J , Teng Teng 
Published: December 2023

Abstract
Homozygous deletion of the MTAP gene is one of the most common genetic alterations in cancer, affecting 10-15% of all human cancer. Clinical MTA-cooperative PRMT5 inhibitors, including TNG908 and TNG462, were developed to leverage the well-characterized synthetic lethal interaction between PRMT5 inhibition and MTAP deletion. Indeed, the first disclosed clinical data for an MTA-cooperative PRMT5 inhibitor demonstrated the ability of TNG908 to selectively inhibit PRMT5 in MTAP-deleted tumors while sparing adjacent normal, MTAP-proficient cells in patients. To further explore the mechanism of action of MTA-cooperative PRMT5 inhibitors in MTAP-deleted cells, we employed multiple CRISPR-based editing platforms (CRISPRn, CRISPRi and CRISPRa) to conduct unbiased MTA-cooperative PRMT5 inhibitor anchor screens in vitro and in vivo. A panel of cancer models representing multiple histologies revealed potential PRMT5 inhibitor sensitization and resistance pathways that also include mechanisms that are specific to MTA-cooperative inhibitors. Specifically, the results of these screens identify 1) the effect of MTA/SAM metabolism on MTA-cooperative PRMT5 inhibitors, and 2) identification of potential sub-stratification strategies for patients with MTAP-deleted cancer, and 3) the activity of PRMT5 in anti-apoptotic pathways and synergy between PRMT5 and BCLxL inhibition.
Citation Format: Steven Lombardo, Matthew R Tonini, Lauren Grove, Silvia Fenoglio, James Tepper, Binzhang Shen, Hannah Stowe, Shangtao Liu, Samuel R Meier, Ashley H Choi, Tenzing Khendu, Yi Yu, Kevin M Cottrell, John P Maxwell, Jannik N Andersen, Alan Huang, Kimberly J Briggs, Teng Teng. Unbiased in vitro and in vivo drug anchor screens identify mechanisms of resistance and sensitization for MTA-cooperative PRMT5 inhibitors in MTAP-deleted cancer 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 B098.
Abstract B102: Predicting small cell lung cancer liver metastasis
Authors: Chrisafis George , Takahashi Nobuyuki , Thomas Anish 
Published: December 2023

Abstract
Small cell lung cancer (SCLC) is a highly aggressive, treatment-resistant form of lung cancer which carries an exceptionally poor prognosis. Patients with SCLC often present at an advanced stage due the propensity of SCLC for early metastasis, with common sites including the brain, liver, adrenal glands, and bone. Liver metastasis has been identified as an independent prognostic factor and is correlated with an unfavorable response to chemotherapy, but specific steps in the liver metastatic cascade have yet to be described. Here, we seek to better characterize SCLC liver metastases by analyzing gene expression data from cell lines and patient biopsy samples. We start by analyzing data published in MetMap (Jin et al., 2020), which calculated organ-specific ‘metastatic potential’ values for cell lines in the Cancer Cell Line Encyclopedia (CCLE). Gene set enrichment analysis of 20 high-grade neuroendocrine differentiated cancer cell lines (8 SCLC, 12 large cell carcinoma) revealed that lines with high liver metastatic potential exhibit significant positive enrichment of genes involved in MYC signaling, oxidative phosphorylation, and xenobiotic metabolism; genes involved in the mitotic spindle and E2F targets are negatively enriched. This hallmark signature appears unique to these cells compared with other non-small cell lung cancer and colorectal cancer. We identify ~45 genes from these hallmarks which are differentially expressed in cell lines with high vs. low liver metastatic potential and create a multiple linear regression model to predict liver metastatic potential based on the expression of these genes. When applied to clinical SCLC samples, the model predicts samples obtained from the liver to have a significantly higher metastatic potential than samples from all other biopsy sites. A higher estimated metastatic potential also correlates with poorer overall survival. Genes and pathways identified by this analysis, following experimental validation, could serve as potential therapeutic targets to disrupt the liver metastatic cascade.
Citation Format: George Chrisafis, Nobuyuki Takahashi, Anish Thomas. Predicting small cell lung cancer liver metastasis [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 B102.
Abstract B110: β3-adrenergic receptor as a new molecular target in neuroblastoma treatment
Authors: Putino Rossana , Boaretto Alessia , Bruno Gennaro , Mattei Gianluca , Tondo Annalisa , Favre Claudio , Calvani Maura 
Published: December 2023

Abstract
Purpose of study: β3-Adrenergic receptor correlation with tumor growth and progression in preclinical and clinical studies in neuroblastoma.
Experimental procedures: Knock-out of β3-Adrenergic Receptor (β3-AR) in Neuroblastoma (NB) cell lines using CRISPR-Cas9 technology. In vivo experiment using β3-AR knock-out cells in order to evaluate the tumor growth in mice. RNA Sequencing of tumor masses derived from mice to investigate β3-AR Dependent tumor signaling pathways. Flow Cytometry analysis to observe the expression level of β3- Adrenergic Receptor on circulating tumor cells (CTCs) in peripheral blood and on disseminated tumor cells (DTCs) in bone marrow from NB patients with low-risk and high-risk prognosis.
Summary of data: CRISPR/Cas9 technology was performed to obtain ADRB3-/- clones from human and murine NB cell lines. ADRB3-/- knocked-out cells were inoculated in murine models NU-Foxn1nu and A/J mice, showing an absence of tumor growth compared to wild type NB cells. Subsequently, RNA sequencing on tumor masses was performed to investigate β3-AR-dependent tumor signaling pathways. RNA-sequencing analysis showed many pathways were altered. Notably, downregulation of genes involved in epithelial–mesenchymal transition (EMT) pathway and genes involved in cell adhesion were underlined in Knock-out vs control, correlated with the absence of tumor growth. Cytofluorimetric analysis of β3-AR level expression were conducted on circulating tumor cells (CTCs) in peripheral blood and on disseminated tumor cells (DTCs) in bone marrow from NB patients with low-risk and high-risk prognosis to evaluating the expression levels of β3-AR. As expected, most of the high-risk NB patients showed high percentage of β3-AR+ cells among CTCs and DTCs, while the majority of low-risk patients showed lower percentage.
Statement of the conclusions: Ours data showed that β3-AR could be a potential target therapy for neuroblastoma treatment. In fact, his deletion results in an absence of tumor growth and progression as demonstrate in mice in vivo experiments. In addition, NB patients with lower β3-AR level, showed a better prognosis . Furter studies should be focused on the pathways related to β3-AR. Moreover, new drugs will be tested in order to normalize the level of β3-AR in NB patients.
Citation Format: Rossana Putino, Alessia Boaretto, Gennaro Bruno, Gianluca Mattei, Annalisa Tondo, Claudio Favre, Maura Calvani. β3-adrenergic receptor as a new molecular target in neuroblastoma treatment [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 B110.
Abstract B129: A bispecific antibody inhibits FGFR3 dimerization and is highly effective in FGFR3-driven tumor models
Authors: Yang Yan , Avvaru Naga Suhasini , Jiang Zaoli , Liu Nina , Rosconi Michael , Zhang Bojie , Li Yinyin , Ullman Erica , Lin John Chia-Yang , Shen Yang , Daly Christopher 
Published: December 2023

Abstract
Background: The receptor tyrosine kinase (RTK) FGFR3 is frequently mutated in bladder cancer (~15-20% in muscle invasive bladder cancer, MIBC) and is a validated therapeutic target. Oncogenic alterations in FGFR3 include point mutations in the extracellular domain (S249C, R248C, G372C, Y375C) and gene fusions that place an oligomerization domain from a fusion partner at the FGFR3 C-terminus (e.g., FGFR3-TACC3). Although pan-FGFR tyrosine kinase inhibitors (TKI) have demonstrated clinical efficacy, toxicity and acquired resistance limit the benefit of these agents. While antibody-based therapy can offer superior selectivity compared to TKIs, conventional ligand-blocking antibodies are usually ineffective inhibitors of constitutively active RTKs. Further, the existence of multiple oncogenic variants of FGFR3 presents an additional challenge for antibody-mediated blockade.
Results: We generated a tetravalent bispecific FGFR3xFGFR3 antibody that potently inhibits both FGFR3 point mutants and fusions with better efficacy than the conventional antibodies that we produced and a clinical-stage comparator antibody. Mechanistically, our bispecific antibody binds FGFR3 through two different epitopes located in immunoglobulin-like domains D1 and D2/3 respectively. It potently blocks the dimerization of FGFR3 S249C, the most common oncogenic variant, inhibiting receptor phosphorylation and downstream signaling. Additionally, our bispecific antibody inhibits the function of FGFR3 gatekeeper mutations (V557M/L) that are resistant to TKIs. In FGFR3-driven tumor models, our antibody is highly effective, providing efficacy similar to that of the FDA-approved TKI erdafitinib.
Conclusion: We have characterized the properties of a tetravalent bispecific FGFR3xFGFR3 antibody that shows strong anti-tumor activity in models driven by FGFR3 S249C as well as by FGFR3-TACC3 fusion, outperforming a conventional antibody that was previously in clinical development. The activity of the bispecific antibody is superior to the mixture of the two parental antibodies and results from strong inhibition of FGFR3 dimerization. Our bispecific antibody provides a novel approach to achieve selective and potent inhibition of multiple oncogenic variants of FGFR3 in bladder cancer, including FGFR3 variants that are resistant to FGFR TKIs.
Citation Format: Yan Yang, Naga Suhasini Avvaru, Zaoli Jiang, Nina Liu, Michael Rosconi, Bojie Zhang, Yinyin Li, Erica Ullman, John Chia-Yang Lin, Yang Shen, Christopher Daly. A bispecific antibody inhibits FGFR3 dimerization and is highly effective in FGFR3-driven tumor 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 B129.
Abstract B133: Anti-tumor efficacy of GMF-1A3-MMAE, an antibody drug conjugate targeting cell surface cleaved Amphiregulin in endocrine-resistant breast cancer
Authors: Lofgren Kristopher A , Kenny Paraic A 
Published: December 2023

Abstract
The Epidermal Growth Factor Receptor ligand, Amphiregulin, is a key proliferative effector of estrogen receptor signaling in breast cancer and also plays a role in other malignancies. Amphiregulin is a single-pass transmembrane protein proteolytically processed by TACE/ADAM17 to release the soluble EGFR ligand, leaving a residual transmembrane stalk that is subsequently internalized. Here, we describe the development of an antibody drug conjugate, GMF-1A3-MMAE, targeting an AREG neo-epitope revealed following ADAM17-mediated cleavage. The antibody does not interact with uncleaved Amphiregulin, providing a novel means of targeting cells with high rates of Amphiregulin shedding. Using fluorescent dye conjugation, we demonstrated that the antibody is internalized by cancer cells in a manner dependent on the presence of cell surface cleaved Amphiregulin. Antibodies conjugated with monomethyl auristatin E (MMAE) were cytotoxic in vitro and induced rapid regression of established breast tumor xenografts in immunocompromised mice. We further demonstrate that these antibodies recognize the Amphiregulin neo-epitope in formalin fixed paraffin embedded tumor tissue, suggesting their utility as a companion diagnostic for patient selection. A pan-cancer tissue microarray analysis indicates that the target is commonly detected at high levels (&gt; 50% of cases) in breast, prostate, liver and lung cancer. In normal tissue microarrays, cleaved Amphiregulin was generally detected at moderate levels in several tissues with only 7 of 93 tissue cores having levels comparable to the high levels commonly found in tumors. These data suggest therapeutic opportunities for GMF-1A3-based ADCs in multiple malignancies, however the broad off-tumor detection of cleaved Amphiregulin suggest linker/payload optimization may be necessary for an adequate therapeutic window.
Citation Format: Kristopher A Lofgren, Paraic A Kenny. Anti-tumor efficacy of GMF-1A3-MMAE, an antibody drug conjugate targeting cell surface cleaved Amphiregulin in endocrine-resistant breast 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 B133.
Abstract B140: Elucidating the novel mechanism of action of VVD-065, an allosteric molecular glue for the KEAP1-CUL3 E3-ligase complex that promotes NRF2 degradation in NRF2-activated cancers
Authors: Snead Aaron , Bernard Steffen , Hee Kenneth , Tran Eileen , Jacinto Sarah , Roy Nil , Wyseure Tine , Pollock Jonathan , Simon Gabe , Kinsella Todd , Weinstein David , Patricelli Matt 
Published: December 2023

Abstract
Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that plays a crucial role in various NRF2-dependent cancers. The protein levels of NRF2 are tightly controlled by a specific E3 ligase complex composed of Kelch-like ECH Associated Protein 1 (KEAP1), Cullin 3 (CUL3), and RING-box protein 1 (RBX1). Under normal conditions, KEAP1 acts as an oxidative sensor and facilitates the ubiquitination and subsequent degradation of NRF2. However, during oxidative or electrophilic stress, KEAP1 can be inactivated through covalent modification of sensor cysteine residues, allowing NRF2 levels to increase and regulate NRF2-dependent genes. In this study, we have elucidated a novel mechanism-of-action for a first-in-class NRF2 inhibitor, VVD-065. Through biochemical and biophysical investigations, we have discovered that VVD-065 functions by covalently interacting with KEAP1 at a sensor cysteine residue, but surprisingly this interaction results in an enhanced affinity between KEAP1 and CUL3, and an increased capacity for Keap1 mediated NRF2 degradation. High-resolution co-crystal structures have revealed that binding of VVD-065 allosterically induces a conformational change that mimics the conformation of KEAP1 when in complex with CUL3. By targeting the KEAP1-CUL3 interaction and promoting the degradation of NRF2, VVD-065 offers a means to modulate NRF2 levels in NRF2-dependent cancers. The unprecedented mechanism of action exhibited by VVD-065 has been confirmed through in vitro and in vivo studies, paving the way for the development of a clinically relevant Keap1 activator.
Citation Format: Aaron Snead, Steffen Bernard, Kenneth Hee, Eileen Tran, Sarah Jacinto, Nil Roy, Tine Wyseure, Jonathan Pollock, Gabe Simon, Todd Kinsella, David Weinstein, Matt Patricelli. Elucidating the novel mechanism of action of VVD-065, an allosteric molecular glue for the KEAP1-CUL3 E3-ligase complex that promotes NRF2 degradation in NRF2-activated 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 B140.