bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1946: Elucidating the mechanisms of acquired resistance to AMG510 in cancer models harboring KRAS G12C mutations
Authors: Ni Ting , Huo Tongxin , Zhang Yawen , Wang Jingjing , Liu Gaoxiang , Shi Wenting , Gu Qingyang 
Published: March 2024

Abstract
GTPase KRas (KRAS), a critical oncogene, is known for its frequent mutations across a wide array of human cancers, most notably in pancreatic, lung, and colorectal cancers. Recent advancements in the field have led to the successful development of numerous inhibitors targeting the mutant KRAS. Clinical application of KRAS G12C inhibitors, such as AMG510 and MTRX849, represents major breakthroughs in addressing previously 'undruggable' cancer targets. Nevertheless, a subset of patients initially responsive to these inhibitors eventually exhibit treatment resistance. Uncovering the underlying mechanism would help to develop novel therapies that overcome the acquired drug resistance.
To elucidate the underlying mechanisms, we generated AMG510-resistant tumor models, namely AMG510-R-MIA PaCa-2 and AMG510-R CT26 KRAS G12C, by continuous administration of AMG510 to tumor-bearing mice. Upon comparison of sensitive parental tumors and resistant tumors, we found that highly expressed KRAS and constant activation of RAS-MAPK signaling pathway are critical for resistant tumor progression following AMG510 treatment. In addition, resistant tumor cells are responsible for the elevated secretion of CXCL2/3/5, which dramatically reconditions the tumor immune microenvironment and recruits immunosuppressive cells.
In summary, the exploration of the resistance mechanism in AMG510-induced resistant models provides insight into the development of new-generation KRAS-G12C inhibitors and novel combinatorial therapies.
Citation Format: Ting Ni, Tongxin Huo, Yawen Zhang, Jingjing Wang, Gaoxiang Liu, Wenting Shi, Qingyang Gu. Elucidating the mechanisms of acquired resistance to AMG510 in cancer models harboring KRAS G12C mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1946.
Abstract 1970: Discovery and characterization of potent and selective HER2 exon20 insertion mutant inhibitors
Authors: Nam Ho Yeon , Jang Sun Young , Jeon Jiyoung , Yoo HyungSeok , Byun Jooyun , Lee Gunwoo , Lee Youngjoo , Kim Yu-Yon , Jeon Soye , Ahn Young Gil 
Published: March 2024

Abstract
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for over 85% of all cases. Among NSCLC, approximately 2-4% of patients have mutations in the HER2, a member of the ErbB family of receptor tyrosine kinases and key proliferation driver, with exon 20 insertions making up about 90% of these mutations. HER2 exon mutations can have various alterations, and among them, the most common HER2 mutation is in-frame insertions in exon 20, especially the A775_G776insYVMA insertion/duplication. These mutations can affect the structure and function of the HER2 protein and may contribute to tumor development and growth. HER2 mutations have often shown resistance to EGFR tyrosine kinase inhibitors (TKIs), further highlighting the need for HER2-specific treatments. Also, inhibitors targeting HER2 mutations are selective, meaning they specifically target HER2 alterations without causing toxicities or affecting EGFRWT. Therefore, there is a need for the development of selective HER2 exon20 insertion mutant inhibitors. Herein, Hanmi has identified selective HER2 exon20 insertion mutant small molecule inhibitors, designed based on affinity and binding mode starting from a known crystal structure using GLIDE (Schrödinger), and the screening for the viability of cell lines including HER2A775_G776insYVMA, HER2G776delinsVC , HER2WT and EGFRWT was investigated. Hanmi's HER2 exon20 insertion mutant inhibitors selectively target mutant HER2 receptor tyrosine domains through shared binding, sparing EGFRWT and minimizing EGFR-related toxicities. With highly selectivity against EGFRWT and desirable pharmacokinetic properties, the Hanmi compounds inhibit HER2 mutant cells and HER2 mutant enzymes. Additionally, the compounds have an oral administration-compatible DMPK profile and demonstrated anti-tumor activity in HER2 mutant and HER2WT tumor xenograft mice. In conclusion, based on our study, Hanmi compounds, a novel HER2 exon20 insertion mutant inhibitors could be suggested as an appropriate therapeutic agent for inhibitory activity against HER2 exon20 insertion mutant NSCLC.
Citation Format: Ho Yeon Nam, Sun Young Jang, Jiyoung Jeon, HyungSeok Yoo, Jooyun Byun, Gunwoo Lee, Youngjoo Lee, Yu-Yon Kim, Soye Jeon, Young Gil Ahn. Discovery and characterization of potent and selective HER2 exon20 insertion mutant inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1970.
Abstract 1975: Discovery of I-1000233, a potent, selective and brain permeable SHP2 allosteric inhibitor
Authors: Puca Francesca , Fabbrini Danilo , Ciammaichella Alina , Missineo Antonino , Bisbocci Monica , Nibbio Martina , Marco Annalise Di , Apicella Claudia , Colaceci Fabrizio , Sasso Romina , Natale Daniela , Scalabrì Francesco , Alli Cristina , Pucci Vincenzo , Montalbetti Christian , Petrocchi Alessia , Carugo Alessandro , Toniatti Carlo 
Published: March 2024

Abstract
Background: SHP2 (Src homology region 2-containing protein tyrosine phosphatase 2) is a target of interest for cancer therapy due to its key role in the regulation of RAS/MAPK signal transduction downstream of Receptor Tyrosine Kinases (RTKs). We report here the identification of I-1000233, a novel, highly potent, orally available and brain permeable SHP2 allosteric inhibitor, with potential for the treatment of tumors with dysregulated RTK/RAS/ERK signaling pathways.
Material and Methods: High-throughput biological, biochemical and pharmacodynamic (PD) assays were used to inform Structure Activity Relationship studies which led to the identification of a chemical series of potent SHP2 inhibitors. Iterative optimization of physicochemical and pharmacological properties resulted in the identification of I-1000233, an orally available SHP2 inhibitor that showed excellent drug-like properties in preclinical studies.
Results: I-1000233 is a potent inhibitor of the SHP2 enzyme in vitro (IC50 = 2 nM) with an exceptionally long residence time on the target. When tested in cell lines, it exhibits significant anti-proliferation activity against brain tumor cells and multiple RAS or EGFR mutant models. It strongly inhibits pERK, a downstream marker of MAPK pathway activity, in a dose dependent manner. Further, in vivo preclinical data confirmed that I-1000233 penetrates the BBB and shows anti-tumor activity, supporting its potential in the treatment of CNS and brain-metastasized tumors.
Conclusions: I-1000233 is a potent, selective and orally available SHP2 inhibitor with potential for once-a-day dosing and its brain permeability in humans makes it a promising therapeutic agent against SHP2i responsive brain tumors and metastases.
Citation Format: Francesca Puca, Danilo Fabbrini, Alina Ciammaichella, Antonino Missineo, Monica Bisbocci, Martina Nibbio, Annalise Di Marco, Claudia Apicella, Fabrizio Colaceci, Romina Sasso, Daniela Natale, Francesco Scalabrì, Cristina Alli, Vincenzo Pucci, Christian Montalbetti, Alessia Petrocchi, Alessandro Carugo, Carlo Toniatti. Discovery of I-1000233, a potent, selective and brain permeable SHP2 allosteric inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1975.
Abstract 2044: A live cell PRMT5 NanoBRET Target Engagement Assay querying competitive and uncompetitive modes of inhibition
Authors: Michaud Ani , Rothweiler Elisabeth , Corona Cesear , Beck Michael , Wilkinson Jennifer , Vasta James , Huber Kilian , Robers Matthew 
Published: March 2024

Abstract
PRMT5 is an essential arginine methyltransferase that regulates a wide spectrum of cellular processes through the methylation of histone and non-histone substrates. In PRMT5 catalysis, SAM serves as the cofactor and methyl group donor, generating a methylated guanidinium moiety on the target substrate. In normal cells, the SAM pools are maintained through the methionine salvage pathway. In 15% of cancers, a key enzyme in this pathway (MTAP) is deleted, leading to an accumulation of the intermediate MTA, which inhibits PRMT5 activity. This genetic loss of function has therefore been pursued as a collateral vulnerability in MTAP deleted cancers. To exploit this synthetic lethality, a number of novel inhibitors have been developed that bind cooperatively at the PRMT5/MTA complex, offering a compelling pathway to precision medicine. Here we describe a novel, live cell NanoBRET Target Engagement assay that enables mechanistic studies on a variety of PRMT5 inhibitors. Using a cell-permeable NanoBRET probe directed to the substrate pocket of PRMT5, both substrate- and cofactor-competitive engagement can be quantified in cells. Moreover, this method can be used to quantify MTA-uncompetitive target engagement in cells, providing a platform to measure the potency of PRMT5-MTA-drug ternary complex formation. This method serves as a first-in-class method to quantify uncompetitive target engagement in live cells, which can be applied to other model systems.
Citation Format: Ani Michaud, Elisabeth Rothweiler, Cesear Corona, Michael Beck, Jennifer Wilkinson, James Vasta, Kilian Huber, Matthew Robers. A live cell PRMT5 NanoBRET Target Engagement Assay querying competitive and uncompetitive modes of inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2044.
Abstract 205: Adaptive membrane trafficking activated by epithelial-to-mesenchymal transition drives lung adenocarcinoma progression
Authors: Obaleye Oluwafunminiyi E. , Fulp Kevin L. , Xiao Guan-Yu 
Published: March 2024

Abstract
Cancer cells can become metastatic and develop resistance to targeted therapies through epithelial-to-mesenchymal transition (EMT), which is regulated by epigenetic factors. Our ultimate objective is to understand the molecular mechanisms behind EMT-driven cancer progression and identify potential targets for preventing cancer metastasis. Recently, we made groundbreaking discoveries indicating that EMT can modify membrane trafficking machinery to coordinate cancer cell invasion and immunosuppression in the tumor microenvironment (TME) of lung adenocarcinoma (LUAD). To dissect the “adaptive” membrane trafficking program, we initiated a CRISPRi in vivo screen to assess more than 2000 trafficking-related genes in syngeneic mouse LUAD models for their requirements for tumorigenesis both with and without immune selective pressure. We identified a panel of membrane trafficking regulators that specifically “dropped out” in immunocompetent mice, suggesting their essential roles in the immunosuppressive TME. Of particular interest is REEP2. REEPs are an evolutionarily conserved protein family that is critical to the endoplasmic reticulum (ER) function and potentially regulates secretory trafficking. We discovered that REEP2 is specifically linked to poor prognosis in LUAD patients and is highly correlated with a z-normalized, 16-gene EMT score (P = 1.32e-27) that was previously reported. Our previous studies demonstrated that the EMT activator, ZEB1, accelerates membrane trafficking dynamics by silencing a microRNA network that targets multiple membrane trafficking components. Analysis of REEP2 3’-untranslated regions (3’-UTRs) identified predicted binding sites for several microRNAs, which are silenced by ZEB1. Thus, we hypothesize that ZEB1 coordinates a microRNA network to activate REEP2-driven ER trafficking. We show that REEP2 depletion significantly reduces the invasion of cancer cells but does not affect their migration and proliferation. These findings suggest that REEP2 plays a significant role in extracellular matrix (ECM) modification to enhance the invasion of metastatic cells, conferring a vulnerability in EMT-driven LUAD metastasis.
Citation Format: Oluwafunminiyi E. Obaleye, Kevin L. Fulp, Guan-Yu Xiao. Adaptive membrane trafficking activated by epithelial-to-mesenchymal transition drives lung adenocarcinoma progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 205.
Abstract 2069: High content imaging without sacrificing coverage, resolution or speed: Functional validation through multiple assays
Authors: Boisvert Matthew , Kieler Josh , DiSepio Dan , Weldon Don 
Published: March 2024

Abstract
Traditionally, high content screening (HCS) required compromise: sacrificing resolution, sample coverage or speed. This has limited high content screening’s utility as a high throughput tool, as speed is essential to cancer research at scale. Using a new approach, Araceli Endeavor® offers a solution to this compromise. This system images 96, 384 or 1536 -well high content microplates in under 10 minutes with full well coverage and sub-micron resolution, enabling high content screening at high throughput speeds without compromising resolution or coverage. Paired with the Clairvoyance™ analysis software, plates are analyzed at similar speeds, going from images to object-level data in 5-25 minutes. As with any new technology, validation is needed. Here we validate Endeavor and Clairvoyance at the level of the bioassay, using a range of common high content assays across different modalities. Assays are chosen to quantifiably demonstrate sensitivity, breadth, and broad applicability. Performance was benchmarked by using well-characterized compounds, matching published EC50/IC50 values when possible. We examined submicron-level nuclear spot counting, measuring histone yH2Ax and micronuclei formation after genotoxic insult. Intensity-based assays include cellular positivity, here live/dead, and subcellular translocation with transcription factor NFΚB after induction with cytokines Il1b and TNFα. Looking at cytosolic vesicle aggregation, we measured autophagic flux with two distinct modalities, comparative imaging and analysis of live cell dye and immunohistochemistry-based detection yielded consistent EC50 values between methods. Overall, these assays yield consistent, robust results corresponding to literature values, showing the importance of full well coverage and resolution. We demonstrate how assays that formerly took hours can be effectively imaged and analyzed without sacrificing quality in 10-30 minutes.
Citation Format: Matthew Boisvert, Josh Kieler, Dan DiSepio, Don Weldon. High content imaging without sacrificing coverage, resolution or speed: Functional validation through multiple assays [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2069.
Abstract 2077: Exploring the multifaceted efficacy of de novo lipogenesis inhibitor in cancer therapy
Authors: Lowder Dallin , Shin Jin Na , Ruiz-Echartea Maria E. , Deng Jenny , Rusin Aleksandra , Skapura Darlene , Ittmann Michael , Kaochar Salma 
Published: March 2024

Abstract
Cancer cells frequently exhibit altered lipid metabolism to sustain their rapid growth and proliferation.Sterol Regulatory Element-Binding Proteins (SREBPs) are key transcription factors that orchestratelipid biosynthesis and uptake in cells. Dysregulation of SREBPs is a common feature of many cancertypes, making them attractive targets for therapeutic intervention. In this study, we present acomprehensive exploration of the potential and rationale for targeting lipid metabolism in cancerthrough the use of a small molecule inhibitor that targets activation of SREBP. We illustrate that oursmall molecule inhibitor (SMI) exhibits potent anticancer activity and effectively targets SREBPsignaling in a variety of prostate cancer models as well as in non-prostate cancer models that arelipogenesis driven. Our novel SMI induces apoptosis and reduces PCa cell proliferation, suppressescell invasion and migration. Furthermore, we illustrate that in addition to suppressing the transcriptionfactor activity of SREBPs, these novel SMIs are highly effective in suppressing both the full length andvariant androgen receptor and their signaling in prostate cancer cells. Notably, in cell and organoidmodels, these novel inhibitors exhibit synergistic anticancer activity in combination with the ARsignaling inhibitor, Enzalutamide. The anticancer activity of these inhibitors extend beyond ARdependent prostate cancer and are also effective in organoid models of neuroendocrine PCa, aparticularly drug-resistant and aggressive PC subtype. Lastly, we illustrate excellent pharmacokineticsand potent anti-tumor effects of these novel SREBP activation inhibitors using in vivo castration-resistant prostate cancer CDX tumors. Given the urgent need for novel targets in PCa, our first-in-class inhibitor represents a promising therapeutic strategy with the potential to effectively targetdysregulated lipogenesis in cancer patients.
Citation Format: Dallin Lowder, Jin Na Shin, Maria E. Ruiz-Echartea, Jenny Deng, Aleksandra Rusin, Darlene Skapura, Michael Ittmann, Salma Kaochar. Exploring the multifaceted efficacy of de novo lipogenesis inhibitor in cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2077.
Abstract 2080: SOS1 inhibition is an effective therapeutic strategy in SOS1-mutant cancer
Authors: Sale Matthew J. , Mukherjee Neal , Koch Martín , Ruzicka Regina , Jacob Robin , Albrecht Christoph , Zanin Teresa , Madensky Thomas , Schenk Robyn L. , Baum Anke , Kostyrko Kaja , Gerlach Daniel , Hofmann Marco H. , McCormick Frank 
Published: March 2024

Abstract
SOS1 is a principal guanine nucleotide exchange factor for canonical RAS GTPases and activates RAS signaling. Mutations in SOS1 are found in several prominent cancer types, including 2-4% of NSCLC, CRC, and melanoma. The recent development of novel SOS1 inhibitors (SOS1i), including BI-3406, that block interaction between SOS1 and RAS, presents a potential therapy for SOS1-driven cancers. Here we show that the majority of SOS1 mutations observed in patients enhance RAS guanine nucleotide exchange in cells and activate RAS-MAPK signaling. We treated 11 SOS1 mutant cancer cell lines without RAS co-mutation with a SOS1i and found that 10 were sensitive to SOS1 inhibition in 2D and/or 3D cell culture. In contrast, cell lines with SOS1 and RAS co-mutations were resistant to SOS1 inhibition. In vitro treatment of SOS1 mutant cells with a SHP2 inhibitor, which is presumed to inhibit the activity of both SOS1 and SOS2, revealed a subset of four cell lines that were more sensitive to SHP2 inhibition than SOS1 inhibition. This implied that, in certain contexts, SOS2 can compensate for the loss of SOS1 activity. Accordingly, these cells exhibited a SOS2-dependent rebound in RAS-MAPK signaling after treatment with SOS1i. SOS2 knock-down further sensitized these cells to SOS1 inhibition, resulting in responses equivalent to SHP2 inhibition. Thus, upon SOS1 inhibition relief of ERK1/2-dependent negative regulation likely contributes to receptor tyrosine kinase-driven SOS2 activation that may mediate SOS1 inhibitor resistance in some contexts. In vivo, SOS1i efficiently inhibited tumor growth in four SOS1-mutant NSCLC, CRC, and AML xenograft models. The tumor-suppressive effects of SOS1i in these models were comparable to or stronger than the effects of SHP2i or MEKi. Thus, our results suggest that SOS1 inhibition could be an effective therapeutic approach in RAS wild-type cancer patients with SOS1 mutations.
Citation Format: Matthew J. Sale, Neal Mukherjee, Martín Koch, Regina Ruzicka, Robin Jacob, Christoph Albrecht, Teresa Zanin, Thomas Madensky, Robyn L. Schenk, Anke Baum, Kaja Kostyrko, Daniel Gerlach, Marco H. Hofmann, Frank McCormick. SOS1 inhibition is an effective therapeutic strategy in SOS1-mutant cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2080.
Abstract 2085: Targeting the translation initiation complex component eIF4G1 in melanoma
Authors: Feng Yongmei , Radaeva Mariia , Kim Hyungsoo , Deshpande Anagha , Deshpande Ani , Jovanovic Predrag , Murad Rabi , Topisirovic Ivan , Olson Steven , Cherkasov Artem , Ronai Ze'ev 
Published: March 2024

Abstract
The translation initiation factor 4F (eIF4F) complex assembly is a rate-limiting step in mRNA translation. eIF4F subunits including eIF4A, eIF4E, and eIF4G, are often upregulated in cancer and neurodegeneration diseases. Elevated eIF4F level/activity has been correlated with poor prognosis and drug resistance. Leveraging our findings with the small molecule SBI-756, which interacts with eIF4G1 and impairs eIF4F complex assembly, we set to map domains that are required for SBI-756 activity. A CRISPR screen using sgRNAs that target different sequences on eIF4G1 led to the identification of the MA3 domain, as a putative binding site for SBI-756. Deletion/mutation of the eIF4G1 MA3 domain attenuated melanoma cells and spheroids growth. Polysome profiling assays confirmed attenuated translation activity, which resembled those seen with SBI-756. In silico virtual screen identified 64 small molecules (out of &gt;10 million) that interact with the MA3 domain. Of these, we have selected four that effectively attenuated melanoma growth in culture. Analogs developed for these four compounds were more potent in impairing the assembly of the eIF4F complex, inhibition of protein translation and the 2D and 3D growth of melanoma cells. RNA-sequencing analysis highlighted altered expression of genes implicated in apoptosis, UPR, cell cycle, and ROS pathways, leading us to test possible combination with pathways that may complement the above. Among those, autophagy inhibitors synergized with our lead compound, M19-6, resulting in efficient melanoma cell death, using notably lower concentrations of these inhibitors. Our findings identify the eIF4G1 MA3 domain as an important player in eIF4F assembly and a potential target for cancer therapy.
Citation Format: Yongmei Feng, Mariia Radaeva, Hyungsoo Kim, Anagha Deshpande, Ani Deshpande, Predrag Jovanovic, Rabi Murad, Ivan Topisirovic, Steven Olson, Artem Cherkasov, Ze'ev Ronai. Targeting the translation initiation complex component eIF4G1 in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2085.