AGER-dependent macropinocytosis drives resistance to KRAS-G12D–targeted therapy in advanced pancreatic cancer

Science Translational Medicine, Journal Year: 2025, Volume and Issue: 17(783)

Published: Jan. 29, 2025

Pancreatic ductal adenocarcinoma (PDAC) driven by the KRAS-G12D mutation presents a formidable health challenge because of limited treatment options. MRTX1133 is highly selective and first-in-class inhibitor under clinical development. Here, we report that advanced glycosylation end product-specific receptor (AGER) plays key role in mediating resistance PDAC cells. The up-regulation AGER within cancer cells instigates macropinocytosis, facilitating internalization serum albumin subsequent amino acid generation. These acids are then used to synthesize antioxidant glutathione, leading due inhibition apoptosis. underlying molecular mechanism involves AGER's interaction with diaphanous-related formin 1 (DIAPH1), protein responsible for driving Rac family small GTPase (RAC1)-dependent macropinosome formation. effectiveness safety combining pharmacological inhibitors AGER-DIAPH1 complex (using RAGE299) or macropinocytosis EIPA) were confirmed patient-derived xenografts, orthotopic models, genetically engineered mouse models. This combination therapy also induces high-mobility group box (HMGB1) release, resulting antitumor CD8+ T cell response immunocompetent mice. Collectively, study findings underscore potential enhance efficacy blockade targeting AGER-dependent macropinocytosis.

Language: Английский

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Targeting pancreatic cancer metabolic dependencies through glutamine antagonism

Nature Cancer, Journal Year: 2023, Volume and Issue: 5(1), P. 85 - 99

Published: Oct. 9, 2023

Abstract Pancreatic ductal adenocarcinoma (PDAC) cells use glutamine (Gln) to support proliferation and redox balance. Early attempts inhibit Gln metabolism using glutaminase inhibitors resulted in rapid metabolic reprogramming therapeutic resistance. Here, we demonstrated that treating PDAC with a antagonist, 6-diazo-5-oxo- l -norleucine (DON), led crisis vitro. In addition, observed profound decrease tumor growth several vivo models sirpiglenastat (DRP-104), pro-drug version of DON was designed circumvent DON-associated toxicity. We found extracellular signal-regulated kinase (ERK) signaling is increased as compensatory mechanism. Combinatorial treatment DRP-104 trametinib significant increase survival syngeneic model PDAC. These proof-of-concept studies suggested broadly targeting could provide avenue for The combination an ERK pathway inhibitor further improve the outcome.

Language: Английский

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A Small Molecule with Big Impact: MRTX1133 Targets the KRASG12D Mutation in Pancreatic Cancer

Clinical Cancer Research, Journal Year: 2023, Volume and Issue: 30(4), P. 655 - 662

Published: Oct. 13, 2023

Abstract KRAS mutations drive oncogenic alterations in numerous cancers, particularly human pancreatic ductal adenocarcinoma (PDAC). About 93% of PDACs have mutations, with G12D (∼42% cases) and G12V (∼32% being the most common. The recent approval sotorasib (AMG510), a small-molecule, covalent, selective KRASG12C inhibitor, for treating patients non–small cell lung cancer represents breakthrough targeted therapy. However, there is need to develop other much-needed KRAS-mutant inhibitors PDAC Notably, Mirati Therapeutics recently developed MRTX1133, noncovalent, KRASG12D inhibitor through extensive structure-based drug design. MRTX1133 has demonstrated potent vitro vivo antitumor efficacy against KRASG12D-mutant cells, especially PDAC, leading its initiation phase I/II clinical trial. Here, we provide summary advancements related use focusing on underlying mechanistic actions. In addition, discuss potential challenges future directions therapy including overcoming intrinsic acquired resistance, developing effective combination therapies, improving MRTX1133’s oral bioavailability target spectrum. promising results obtained from preclinical studies suggest that could revolutionize treatment bringing about paradigm shift management.

Language: Английский

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Early Diagnosis and Prognosis Prediction of Pancreatic Cancer Using Engineered Hybrid Core‐Shells in Laser Desorption/Ionization Mass Spectrometry

Advanced Materials, Journal Year: 2024, Volume and Issue: 36(18)

Published: Jan. 19, 2024

Abstract Effective detection of bio‐molecules relies on the precise design and preparation materials, particularly in laser desorption/ionization mass spectrometry (LDI‐MS). Despite significant advancements substrate performance single‐structured substrates remains suboptimal for LDI‐MS analysis complex systems. Herein, designer Au@SiO 2 @ZrO core‐shell are developed LDI‐MS‐based early diagnosis prognosis pancreatic cancer (PC). Through controlling Au core size ZrO shell crystallization, signal amplification metabolites up to 3 orders is not only achieved, but also synergistic mechanism LDI process revealed. The optimized enables a direct record serum metabolic fingerprints (SMFs) by LDI‐MS. Subsequently, SMFs employed distinguish PC (stage I/II) from controls, with an accuracy 92%. Moreover, prognostic prediction scoring system established enhanced efficacy predicting survival compared CA19‐9 (p < 0.05). This work contributes material‐based prognosis.

Language: Английский

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The Roles and Interactions of Porphyromonas gingivalis and Fusobacterium nucleatum in Oral and Gastrointestinal Carcinogenesis: A Narrative Review

Pathogens, Journal Year: 2024, Volume and Issue: 13(1), P. 93 - 93

Published: Jan. 20, 2024

Epidemiological studies have spotlighted the intricate relationship between individual oral bacteria and tumor occurrence. Porphyromonas gingivalis Fusobacteria nucleatum, which are known periodontal pathogens, emerged as extensively studied participants with potential pathogenic abilities in carcinogenesis. However, complex dynamics arising from interactions these two pathogens were less addressed. This narrative review aims to summarize current knowledge on prevalence mechanism implications of P. F. nucleatum carcinogenesis squamous cell carcinoma (OSCC), colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC). In particular, it explores clinical experimental evidence interplay affecting gastrointestinal recognized keystone or bridging bacteria, identified multiple simultaneously. The both species correlated development progression, emphasizing impact collaboration. Regrettably, there was insufficient demonstrate synergistic function. We further propose a hypothesis elucidate underlying mechanisms, offering promising avenue for future research this dynamic evolving field.

Language: Английский

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Activation of the PI3K/AKT signaling pathway by ARNTL2 enhances cellular glycolysis and sensitizes pancreatic adenocarcinoma to erlotinib

Molecular Cancer, Journal Year: 2024, Volume and Issue: 23(1)

Published: March 8, 2024

Abstract Background Pancreatic adenocarcinoma (PC) is an aggressive malignancy with limited treatment options. The poor prognosis primarily stems from late-stage diagnosis and when the disease has become therapeutically challenging. There urgent need to identify specific biomarkers for cancer subtyping early detection enhance both morbidity mortality outcomes. addition of EGFR tyrosine kinase inhibitor (TKI), erlotinib, gemcitabine chemotherapy first-line patients advanced pancreatic slightly improved However, restricted clinical benefits may be linked absence well-characterized criteria stratification dependable prediction effectiveness. Methods results We examined levels various hallmarks identified glycolysis as primary risk factor overall survival in PC. Subsequently, we developed a glycolysis-related score (GRS) model accurately distinguish PC high GRS. Through silico screening 4398 compounds, discovered that erlotinib had strongest therapeutic high-GRS patients. Furthermore, ARNTL2 novel prognostic biomarker predictive responsiveness Inhibition expression reduced efficacy, whereas increased cell sensitivity erlotinib. Validation vivo using patient-derived xenografts (PDX-PC) varying demonstrated monotherapy effectively halted tumor progression PDX-PC models expression. In contrast, lacking did not respond favorably treatment. Mechanistically, ARNTL2/E2F1 axis-mediated cellular sensitizes cells by activating PI3K/AKT signaling pathway. Conclusions Our investigations have indicator sensitivity. These will help erlotinib-responsive cases improve findings contribute advancement precision oncology, enabling more accurate targeted interventions.

Language: Английский

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Emerging mechanisms and promising approaches in pancreatic cancer metabolism

Cell Death and Disease, Journal Year: 2024, Volume and Issue: 15(8)

Published: Aug. 1, 2024

Abstract Pancreatic cancer is an aggressive with a poor prognosis. Metabolic abnormalities are one of the hallmarks pancreatic cancer, and cells can adapt to biosynthesis, energy intake, redox needs through metabolic reprogramming tolerate nutrient deficiency hypoxic microenvironments. use glucose, amino acids, lipids as maintain malignant growth. Moreover, they also metabolically interact in tumour microenvironment change cell fate, promote progression, even affect immune responses. Importantly, changes at body level deserve more attention. Basic research clinical trials based on targeted therapy or combination other treatments full swing. A comprehensive in-depth understanding regulation will not only enrich mechanisms disease progression but provide inspiration for new diagnostic therapeutic approaches.

Language: Английский

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Oncogenic KRAS-Dependent Stromal Interleukin-33 Directs the Pancreatic Microenvironment to Promote Tumor Growth

Cancer Discovery, Journal Year: 2024, Volume and Issue: 14(10), P. 1964 - 1989

Published: July 3, 2024

Abstract Pancreatic cancer is characterized by an extensive fibroinflammatory microenvironment. During carcinogenesis, normal stromal cells are converted to cytokine-high cancer-associated fibroblasts (CAF). The mechanisms underlying this conversion, including the regulation and function of fibroblast-derived cytokines, poorly understood. Thus, efforts therapeutically target CAFs have so far failed. Herein, we show that signals from epithelial expressing oncogenic KRAS—a hallmark pancreatic mutation—activate fibroblast autocrine signaling, which drives expression cytokine IL33. Stromal IL33 remains high dependent on KRAS throughout carcinogenesis; in turn, environmental stress induces interleukin-33 (IL33) secretion. Using compartment-specific knockout mice, observed lack leads profound reprogramming multiple components tumor microenvironment, CAFs, myeloid cells, lymphocytes. Notably, loss increase CD8+ T-cell infiltration activation and, ultimately, reduced growth. Significance: This study provides new insights into programming shows during process, induced. CAF-derived has pleiotropic effects supporting its potential as a therapeutic target.

Language: Английский

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Electrochemiluminescence biosensor for specific detection of pancreatic ductal carcinoma through dual targeting of MUC1 and miRNA-196a

Biosensors and Bioelectronics, Journal Year: 2024, Volume and Issue: 254, P. 116241 - 116241

Published: March 23, 2024

Language: Английский

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The MUC1–HIF-1α signaling axis regulates pancreatic cancer pathogenesis through polyamine metabolism remodeling

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(14)

Published: March 28, 2024

Dysregulation of polyamine metabolism has been implicated in cancer initiation and progression; however, the mechanism dysregulation is not fully understood. In this study, we investigated role MUC1, a mucin protein overexpressed pancreatic cancer, regulating metabolism. Utilizing patient data, noted positive correlation between MUC1 expression key pathway genes. Functional studies revealed that knockdown spermidine/spermine N1-acetyltransferase 1 ( SAT1 ), enzyme involved catabolism, attenuated oncogenic functions including cell survival proliferation. We further identified regulatory axis whereby stabilized hypoxia-inducible factor (HIF-1α), leading to increased expression, which turn induced carbon flux into tricarboxylic acid cycle. MUC1-mediated stabilization HIF-1α enhanced promoter occupancy latter on corresponding transcriptional activation , could be abrogated by pharmacological inhibition or CRISPR/Cas9-mediated knockout HIF1A . caused significant reduction levels SAT1-generated metabolites, N1-acetylspermidine N8-acetylspermidine. Given known therapy resistance, also whether inhibiting would enhance efficacy FOLFIRINOX chemotherapy. By utilizing organoid orthotopic mouse models, observed targeting with pentamidine improved FOLFIRINOX, suggesting combination may represent promising therapeutic strategy against cancer. This study provides insights interplay metabolism, offering potential avenues for development treatments

Language: Английский

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