bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A022: Translation initiation factor 2B (eIF2B) stimulates mutant KRAS function in cancer
Authors: Kim Hyungdong , Ghaddar Nour , Ghahnavieh Laleh Ebrahimi , Wang Shuo , Cho Kwang-Jin , Sasaki Atsuo , Koromilas Antonis E. 
Published: May 2023

Abstract
KRAS mutations appear with high frequency in colorectal, lung and pancreatic cancers, which are the three leading causes of new cancer deaths worldwide. Mutant KRAS is preferentially bound to GTP resulting in continuous cell proliferation. Mutant KRAS exposes cells to oncogenic forms of stress (i.e. genotoxic, metabolic, proteostatic stress), which disrupt proliferation and tissue homeostasis. To cope with stress, cells engage pro-adaptive mechanisms, which act in favor of mutant KRAS to transform cells. An important adaptation mechanism to stress acts at the level of mRNA translation and involves the functional interplay between the translation initiator factors eIF2 and eIF2B. Phosphorylated eIF2 mediates a translational and transcriptional reprogramming to promote adaptation under stress, a process that is antagonized by the guanine exchange function (GEF) of eIF2B. We demonstrate the physical interaction between mutant KRAS and eIF2B by mass spectrometry. Using genetic approaches, we show that eIF2B is required for the survival and proliferation of tumor cells with KRAS mutations via the stimulation of MAPK signaling. We also show that eIF2B contributes to increased resistance of tumor cells to pharmacological inhibition of mutant KRAS forms. Genetic inactivation of eIF2B promotes the formation of mutant KRAS-GDP complexes whereas its pharmacological stimulation facilitates mutant KRAS-GTP complex formation in tumor cells; this data supports a potential GEF function for eIF2B towards mutant KRAS. Cell imaging experiments provide strong evidence for the implication of eIF2B in the association of mutant KRAS with the plasma membrane of tumor cells. Our findings reveal a stimulatory role of eIF2B in mutant KRAS signaling and provide a previously unidentified link between mutant KRAS and mRNA translation with implications in the growth and treatment of cancers with KRAS mutations.
Citation Format: Hyungdong Kim, Nour Ghaddar, Laleh Ebrahimi Ghahnavieh, Shuo Wang, Kwang-Jin Cho, Atsuo Sasaki, Antonis E. Koromilas. Translation initiation factor 2B (eIF2B) stimulates mutant KRAS function in cancer [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr A022.
Abstract A023: Structural basis for regulation of MAPK signaling by DUSP5 and DUSP6
Authors: Kung Jennifer E. , Sudhamsu Jawahar 
Published: May 2023

Abstract
The Ras/mitogen-activated protein kinase (MAPK) cascade plays an essential role in several critical cellular processes, such as cell growth and proliferation, and hyperactivation of this pathway is frequently observed in cancer. DUSP5 and DUSP6 are dual specificity phosphatases (capable of dephosphorylating phospho-tyrosines as well as phospho-serines/threonines) that act as key regulators of MAPK signaling that inactivate ERK by dephosphorylating its activation loop and sequestering ERK in an inactive state. DUSP5 and DUSP6 have been reported to function as tumor suppressors in some Ras-driven cancers, including skin cancer and pancreatic cancer, while promoting tumorigenesis in other contexts, such as thyroid cancer or glioblastoma. Despite the importance of these phosphatases in modulating ERK signaling, the structural basis for their interaction with ERK and their dual specificity remain poorly understood. It has also been reported that ERK binding allosterically activates DUSP6, but not DUSP5, and the mechanism underlying this is unclear. While structures of individual domains of these proteins have been solved, there are no structures of full-length DUSP5 or DUSP6, or of an ERK/DUSP complex. To gain insight into the molecular determinants of ERK dephosphorylation by these phosphatases, we have purified full-length DUSP5 and DUSP6, as well as the phosphatase domains of both proteins. We have also generated full-length phosphorylated ERK2 (pERK2). Through in vitro dephosphorylation assays, we have observed that full-length DUSP5 and DUSP6 dephosphorylate ERK2 much more rapidly than the isolated phosphatase domains, indicating an essential role for their N-terminal regulatory domains in this process. Using biolayer interferometry, we show that catalytically inactive mutants of full-length DUSP5 and DUSP6 bind very tightly to pERK2 with low nanomolar affinity. We have reconstituted complexes of pERK2 bound to catalytically inactive full-length DUSP5 or DUSP6, and we are pursuing structures of these complexes using x-ray crystallography and cryo-electron microscopy. These studies will improve our understanding of the regulation of ERK and its phosphatases DUSP5 and DUSP6 and shed light on the similarities and differences between these complexes. These structures could also potentially reveal the structural features underlying the dual specificity of DUSP5 and DUSP6.
Citation Format: Jennifer E. Kung, Jawahar Sudhamsu. Structural basis for regulation of MAPK signaling by DUSP5 and DUSP6 [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr A023.
Abstract A025: Investigating the molecular mechanisms of regulation of the RAS guanine nucleotide exchange factor, SOS1 by Grb2 and 14-3-3
Authors: Martinez Orlando E. , Sudhamsu Jawahar 
Published: May 2023

Abstract
The MAPK/ERK signaling pathway is one of the most heavily mutated in human cancers. In normal cells, the stimulation of receptor tyrosine kinases (e.g. EGFR) on the plasma membrane signals the GTP-loading and activation of RAS through a mechanism catalyzed by the guanine nucleotide exchange factor (GEF) Son of Sevenless 1 (SOS1). RAS activation, in turn, initiates the RAF-MEK-ERK kinase cascade which triggers many downstream signals that can affect gene transcription, protein translation, cell proliferation, and feedback regulation. Several factors regulate SOS1 GEF activity, including two autoinhibitory domains within its own multi-domain architecture. First, the N-terminal domains of SOS1 occlude the allosteric RAS-GTP binding site in the RAS exchanger motif—thereby precluding SOS1 GEF activity—and this inhibition is relieved upon membrane recruitment and PIP2 phospholipid binding. Second, the C-terminal Proline-Rich Region (PRR) of SOS1 also occludes allosteric RAS-GTP binding by an unknown mechanism and is relieved when the growth factor receptor-bound protein 2 (Grb2) binds to motifs in the PRR. While the independent functions of these domains and interactions to inhibition and activation of GEF activity of SOS1 are known, the molecular mechanisms are poorly understood. An additional negative feedback loop involves the phosphorylation of the SOS1 PRR at two sites by the ribosomal protein S6 kinase 1 (RSK1), a substrate of downstream ERK. These modifications create 14-3-3 binding sites on SOS1, where 14-3-3 binding downregulates GEF activity, possibly by obstructing Grb2 association with the SOS1 PRR and membrane localization of SOS1. This work reconstitutes the SOS1:Grb2 and the SOS1:14-3-3 protein complexes in vitro to study the molecular mechanisms underlying SOS1 activity regulation.
Citation Format: Orlando E. Martinez, Jawahar Sudhamsu. Investigating the molecular mechanisms of regulation of the RAS guanine nucleotide exchange factor, SOS1 by Grb2 and 14-3-3 [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr A025.
Abstract A037: Oncogenic RAS signals from lysosomes to activate mTORC1 in multiple myeloma
Authors: Bolomsky Arnold , Young Ryan M. 
Published: May 2023

Abstract
Oncogenic mutations of both NRAS and KRAS are common in multiple myeloma (MM), an incurable malignancy of plasma cells. However, the mechanisms of pathogenic RAS signaling in MM have remained enigmatic, and there is little evidence to support a dominant role for classical MAPK signaling downstream of RAS in this disease. We recently used an unbiased proteogenomic approach to dissect RAS signaling in MM and discover that mutant isoforms of RAS organized a signaling complex with the amino acid transporter, SLC3A2, and MTOR on lysosomes, which directly activated mTORC1 by co-opting amino acid sensing pathways (PMID: 36115844). To gain further insights into this novel mode of RAS signaling located away from the plasma membrane, we have employed mass spectrometry to characterize proteins associated with lysosomes isolated from MM cell lines. We observed that RAS isoforms, SLC3A2 and several components of the mTORC1 signalosome were purified with lysosomes, consistent with RAS activation of mTORC1 on lysosomes. To identify novel regulators of oncogenic RAS signaling at the lysosome, we used phospho-proteomics to identify proteins with significantly reduced levels of phosphorylation following acute inhibition of KRAS activity with the KRAS G12D inhibitor, MRTX1133, in a MM cell line bearing a KRAS G12D mutation. Many of these phospho-proteins were also associated with lysosomes, including MTOR, which had substantially reduced phosphorylation at the amino-acid dependent phosphorylation site S1261 following KRAS inhibition. Pathway analysis of proteins present in lysosomes and phosphorylated downstream of oncogenic KRAS showed enrichment for proteins that regulate intracellular trafficking. Among these proteins, we found that disruption of a RAB GAP essential for survival in RAS-dependent MM cells substantially reduced associations between RAS and MTOR and nearly abolished RAS-dependent mTORC1 activity. These data suggest that mutant RAS utilizes lysosomal resident proteins to coordinate the colocalization of itself with mTORC1 on lysosomes to drive pathogenic signaling in MM. More generally, these studies suggest that targeting the intracellular localization of RAS may be an alternative route to inhibit oncogenic RAS signaling in MM.
Citation Format: Arnold Bolomsky, Ryan M. Young. Oncogenic RAS signals from lysosomes to activate mTORC1 in multiple myeloma [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr A037.
Abstract B022: A non-conserved histidine residue on KRAS drives paralog selectivity of the KRAS G12D inhibitor MRTX1133
Authors: Keats Miles , Han John , Lee Yeon-Hwa , Lee Chih-Shia , Luo Ji 
Published: May 2023

Abstract
The discovery of small molecule inhibitors against mutant KRAS protein has been a breakthrough in targeted therapy. MRTX1133 is the first non-covalent inhibitor with selectivity for the mutant KRAS G12D protein. Using isogenic cell lines expressing single Ras allele to test the selectivity of this compound, we found that in addition to KRAS G12D, MRTX1133 shows significant activity against several other KRAS mutants as well as wildtype KRAS protein. In contrast, MRTX1133 exhibits no activity against both G12D and wildtype forms of HRAS and NRAS proteins. Functional analysis revealed that the selectivity of MRTX1133 towards KRAS is associated with its binding to histidine 95 on KRAS, a residue that is not conserved in HRAS and NRAS. Reciprocal mutation of amino acid 95 among the three Ras paralogs resulted in reciprocal change in their sensitivity towards MRTX1133. Thus, histidine 95 is an essential selectivity handle for MRTX1133 towards KRAS. This knowledge could aid the development of other KRAS-selective inhibitors. (Funding: this research was supported by the Intramural Research Program of the National Cancer Institute, NIH)
Citation Format: Miles Keats, John Han, Yeon-Hwa Lee, Chih-Shia Lee, Ji Luo. A non-conserved histidine residue on KRAS drives paralog selectivity of the KRAS G12D inhibitor MRTX1133 [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr B022.
Abstract IA05: Uncovering new structural insights into RAS interactions with effectors and regulators
Authors: Simanshu Dhirendra K. 
Published: May 2023

Abstract
RAS proteins, which act as binary molecular switches, are implicated in approximately 20% of all cancer cases and are known to play a critical role in the initiation and progression of some of the deadliest cancers, such as lung, colon, and pancreatic cancers. When RAS proteins are in the GTP-bound state, they interact with various effector proteins, such as RAF Kinase, PI 3-Kinase, and RalGDS, leading to the activation of multiple signaling pathways in the cell. Our recent structural studies, including investigations into the KRAS-SIN1 (RBD-PH domain), KRAS-RAF1 (RBD-CRD), and SHOC2-MRAS-PP1C complex, have provided new insights into the vital role played by the switch-II and interswitch regions in the interaction between RAS and downstream effectors and regulators. These findings extend beyond the earlier observations that the switch-I region of RAS proteins alone plays a more significant role in RAS-effector interactions. Furthermore, research into the KRAS4a-SIN1 complex and the reported interaction between KRAS4a and hexokinase have given us a glimpse into the isoform-specific RAS-effector interaction. Finally, the investigation of the SHOC2-MRAS-PP1C complex has also revealed the crucial role played by other members of the RAS subfamily, such as MRAS, in RAF activation by canonical RAS isoforms. Collectively, these studies have shed new light on the mechanisms by which RAS interacts with downstream effectors and regulators.
Citation Format: Dhirendra K. Simanshu. Uncovering new structural insights into RAS interactions with effectors and regulators [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr IA05.
Abstract IA13: Identifying metabolic dependencies in pancreatic cancer
Authors: Kimmelman Alec 
Published: May 2023

Abstract
Pancreatic cancers are highly resistant to currently available therapeutics which results in a 5-year survival rate of approximately 11%. We believe that this resistance points toward altered cell metabolic pathways. In this regard we have previously shown that that oncogenic Kras promotes a rewiring of pancreatic cancer metabolism allowing carbon sources to be utilized in a variety of biosynthetic pathways. Importantly, several of these metabolic pathways are critical for tumor growth and therefore represent potential therapeutic targets. Ongoing studies from our group are exploring targeting various aspects of metabolism as therapeutic approaches. Additional studies from our group have demonstrated pancreatic cancers have elevated basal autophagy which is required for their continued growth. Importantly, inhibition of autophagy pharmacologically or genetically leads to decreased oxidative phosphorylation, a drop in ATP production, and ultimately growth inhibition. These findings have implicated autophagy as a key component of pancreatic cancer metabolism and have motivated the opening of multiple clinical trials assessing the efficacy of hydroxychloroquine as an autophagy inhibitor in pancreatic cancer, which have now shown clinical activity in pancreatic cancer patients. Recently, we have identified a novel selective autophagy pathway that degrades MHC-I and promotes immune evasion in pancreatic tumors. Ongoing work from our group seeks to understand the metabolic contributions that autophagy makes in pancreatic tumors. These and other aspects of pancreatic cancer metabolism will be discussed.
Citation Format: Alec Kimmelman. Identifying metabolic dependencies in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr IA13.
Abstract A39: Role of LARP1 in the leukemogenesis of Acute Myeloid Leukemia
Authors: Nahotko Dominik A , Baran Aneta H , Fischietti Mariafausta , Beauchamp Elspeth M , Platanias Leonidas C 
Published: May 2023

Abstract
Mammalian target of rapamycin (mTOR) is a strong driver of tumorigenesis in multiple types of tumors, however targeting mTOR for cancer therapy has yielded only limited success. This may be explained in part by signaling redundancy with other pathways, such as CDK9 mTOR-Like (CTORC) complexes, recently described by our group. One of the binders common to mTORC1 and CTORC2 is La related protein 1 (LARP1). LARP1 influences ribosome biogenesis by regulating translation of 5'terminal oligopyrimidine tract (5’ TOP) containing mRNAs, which often encode ribosomal proteins and translation factors. Here, we validate LARP1 as common target of mTORC1 and CTORC2 as well as investigate its influence on leukemogenesis. To explore LARP1’s role in leukemogenesis we utilized CRISPR/CAS9 technology to create OCI-AML5 and U937 LARP1 knockout (KO) cells. Loss of LARP1 expression significantly diminished proliferation potential of AML cell lines both in vitro as well as in vivo when implanted into the flank of athymic nude mice as xenografts. Additionally, primary CD34+ leukemia cells were transfected with LARP1 targeting or scrambled siRNA and leukemic progenitor growth was assessed in methocellulose colony formation assays. We observed suppression of leukemic progenitors colony forming ability in LARP1 siRNA transfected cells, compared to the Ctrl siRNA transfected cells. We also determined enhanced sensitivity of Larp1 KO cell lines to standard chemotherapy agents such Azacitidine, Cytarabine and Venetoclax. We employed polysome profiling to compare global translation levels between Larp1 KO and control U937 cells. Our polysomal profiling results show that KO of LARP1 in U937 cells reduces global translation and ribosome biogenesis as expected as we observed a suppression of both monosomal and polysomal peaks. In summary, Larp1 is important for leukemogenesis and influences their response to treatment with currently used chemotherapy agents. These observations together suggest that LARP1 is a promising target for development of novel antileukemia approaches.
Citation Format: Dominik A Nahotko, Aneta H Baran, Mariafausta Fischietti, Elspeth M Beauchamp, Leonidas C Platanias. Role of LARP1 in the leukemogenesis of Acute Myeloid Leukemia [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr A39.
Abstract IA22: Myeloproliferative neoplasms: Inflammation and treatment
Authors: Mesa Ruben 
Published: May 2023

Abstract
Myeloproliferative neoplasms have a prevalence of around 350,000 in the USA and include the diagnoses of essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF). These clonal neoplasms share core set of acquired driver mutations in JAK2, calreticulin (CALR), and MPL which all lead to constitutive activation of the JAK-STAT pathway. Additionally, a range of somatic mutations may occur which impact disease phenotype as risk of progression (such as ASXL1, IDH 1 & 2, EZH2 2 etc). The burden of these illnesses include a predisposition to thrombosis or bleeding, a range of challenging symptoms (from spleen pain, to hypermetabolic symptoms, pruritus, fatigue, bone pain), splenomegaly, cytopenias, and potential progression to acute myeloid leukemia. Although the origin of these diseases are anchored in a clonal neoplastic process, inflammation potentially plays a role in the risk of thrombosis, the origin of many of the difficult symptoms, potential contribution to cytopenias, and the potential risk of progression from ET/PV to MF, or from MF to AML. A spectrum of cytokines have been found to be elevated in MPNs (especially in MF), with elevation of certain ones negatively impacting prognosis including IL-8, IL-2R, IL-12, IL-15. Therapy of MPNs now includes non-specific cytoreduction (i.e. hydroxyurea for ET-PV), long acting interferons (i.e. ropegylated interferon a2b for polycythemia vera), and JAK inhibition with ruxolitinib (inhibits JAK1 and JAK2), fedratinib (JAK2 and FLT3), pacritinib (inhibits JAK2, FLT3, IRAK1, and ACVR1), and momelotinib (inhibits JAK1, JAK2, ACVR1). The JAK inhibitors have made a significant impact on decreasing the burden MPN patients face by decreasing splenomegaly (and its associated symptom burden), by decreasing MPN associated symptoms, and by improving survival. The mechanism of improved survival is not fully understood but may include a decrease in marrow inflammation and perhaps decreasing the mutagenic pressure that leads to additional somatic mutations such as ASXL1 that leads to AML. Hepcidin associated with inflammation is dually being investigated as means to decrease erythrocytosis in PV with hepcidin mimetics (i.e. rusferatide), and to improve MF associated anemia by inhibiting hepcidin (momelotinib or pacritinib by ACVR1 inhibition). Inflammation as both a driver of disease burden and progression, as well as a viable therapeutic target remains an important focus of investigation and interventional trials.
Citation Format: Ruben Mesa. Myeloproliferative neoplasms: Inflammation and treatment [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr IA22.
ВПЛИВ КЕРОВАНИХ ЧИННИКІВ РИЗИКУ НА РОЗВИТОК ОНКОЛОГІЧНОЇ ПАТОЛОГІЇ В УКРАЇНІ ТА СВІТІ
Authors: Теренда Н. О. , Сатурська Г. С. , Шульгай А. Г. , Панчишин Н. Я. , Петрашик Ю. М. , Слободян Н. О. , Трущенкова Л. В. , Литвинова О. Н. , Запорожан Л. П. , Смірнова В. Л. , Романюк Л. М. , Романюк Н. Є. 
Published: May 2023

Мета: провести порівняльну оцінку в загальному тягарі смертей основних ризиків глобального тягаря раку.
Матеріали і методи. В дослідженні використано результати даних бази глобального тягаря хвороб (Global Burden of Disease – GBD), національного канцер-реєстру України. Використано методи порівняльного аналізу, системного підходу та системного аналізу, бібліосемантичний та медико-статистичний методи.
Результати. За даними GBD 2019 р., серед причин смерті для чоловіків у світі та в Україні найбільш поширеними були: рак трахеї, бронхів і легень, рак товстої і прямої кишок, рак шлунка, рак простати, рак стравоходу та рак печінки. Серед жінок найбільшою смертність як у світі, так і в Україні є смертність від раку молочної залози. Наступними за питомою часткою у світі за кількістю смертей у жінок є рак трахеї, бронхів і легень, рак товстої і прямої кишок, рак шлунка та рак шийки матки. При порівнянні із світовим рівнем смертність від перелічених форм раку в Україні у чоловіків та жінок, окрім смертності від раку товстої і прямої кишок, нижча. При цьому також спостерігається зростання смертності від вказаних нозологій з 2015 до 2019 р.
Виявлено вищі показники атрибутивного ризику смертей при більшості нозологічних форм раку серед населення України (рак бронхів, трахеї і легень, раку гортані, глотки, губи та стравоходу). Екологічні та професійні чинники в Україні не переважають показники впливу на глобальному рівні, а серед деяких нозологій онкопатології визначаються нижчими, зокрема рак бронхів, трахеї та легень і рак гортані. В Україні метаболічні чинники, на відміну від світових тенденцій, переважають серед ризиків смертності хворих на рак печінки, стравоходу, матки та нирки.
Висновки. За період 2015–2019 рр. в Україні та світі спостерігається зростання частки смертей від найпоширеніших форм раку. Керовані чинники ризику розвитку онкологічної патології мають високі показники атрибутивного ризику. З них найбільш виражений вплив як у всьому світі, так і в Україні мають поведінкові чинники.