Protein degraders enter the clinic — a new approach to cancer therapy

Nature Reviews Clinical Oncology, Journal Year: 2023, Volume and Issue: 20(4), P. 265 - 278

Published: Feb. 13, 2023

Language: Английский

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RAB31 marks and controls an ESCRT-independent exosome pathway

Cell Research, Journal Year: 2020, Volume and Issue: 31(2), P. 157 - 177

Published: Sept. 21, 2020

Abstract Exosomes are generated within the multivesicular endosomes (MVEs) as intraluminal vesicles (ILVs) and secreted during fusion of MVEs with cell membrane. The mechanisms exosome biogenesis remain poorly explored. Here we identify that RAB31 marks controls an ESCRT-independent pathway. Active RAB31, phosphorylated by epidermal growth factor receptor (EGFR), engages flotillin proteins in lipid raft microdomains to drive EGFR entry into form ILVs, which is independent ESCRT (endosomal sorting complex required for transport) machinery. interacts SPFH domain drives ILV formation via Flotillin proteins. Meanwhile, recruits GTPase-activating protein TBC1D2B inactivate RAB7, thereby preventing lysosomes enabling secretion ILVs exosomes. These findings establish has dual functions exosomes: driving suppressing degradation, providing exquisite framework better understand biogenesis.

Language: Английский

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Suppression of the SLC7A11/glutathione axis causes synthetic lethality in KRAS-mutant lung adenocarcinoma

Journal of Clinical Investigation, Journal Year: 2019, Volume and Issue: 130(4), P. 1752 - 1766

Published: Dec. 24, 2019

Oncogenic KRAS is a major driver in lung adenocarcinoma (LUAD) that has yet to be therapeutically conquered. Here we report the SLC7A11/glutathione axis displays metabolic synthetic lethality with oncogenic KRAS. Through metabolomics approaches, found mutationally activated strikingly increased intracellular cystine levels and glutathione biosynthesis. SLC7A11, cystine/glutamate antiporter conferring specificity for uptake, was overexpressed patients KRAS-mutant LUAD showed positive association tumor progression. Furthermore, SLC7A11 inhibition by either genetic depletion or pharmacological sulfasalazine resulted selective killing across panel of cancer cells vitro growth vivo, suggesting functionality as therapeutic target. Importantly, further identified potent inhibitor, HG106, markedly decreased uptake HG106 exhibited cytotoxicity toward increasing oxidative stress- ER stress-mediated cell apoptosis. Of note, treatment several preclinical mouse models led marked suppression prolonged survival. Overall, our findings reveal are vulnerable inhibition, offering potential approaches this currently incurable disease.

Language: Английский

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Rational combinations of targeted cancer therapies: background, advances and challenges

Nature Reviews Drug Discovery, Journal Year: 2022, Volume and Issue: 22(3), P. 213 - 234

Published: Dec. 12, 2022

Language: Английский

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Polytherapy and Targeted Cancer Drug Resistance

Trends in cancer, Journal Year: 2019, Volume and Issue: 5(3), P. 170 - 182

Published: Feb. 26, 2019

Language: Английский

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Targeted therapy for hepatocellular carcinoma: Challenges and opportunities

Cancer Letters, Journal Year: 2019, Volume and Issue: 460, P. 1 - 9

Published: June 15, 2019

Language: Английский

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Streptomyces: The biofactory of secondary metabolites

Frontiers in Microbiology, Journal Year: 2022, Volume and Issue: 13

Published: Sept. 29, 2022

Natural products derived from microorganisms serve as a vital resource of valuable pharmaceuticals and therapeutic agents. Streptomyces is the most ubiquitous bacterial genus in environments with prolific capability to produce diverse natural significant biological activities medicine, environments, food industries, agronomy sectors. However, many remain unexplored among . It exigent develop novel antibiotics, agrochemicals, anticancer medicines, etc., due fast growth resistance cancer chemotherapeutics, pesticides. This review article focused secreted by their function importance curing diseases agriculture. Moreover, it discussed genomic-driven drug discovery strategies also gave future perspective for development

Language: Английский

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Metformin induces human esophageal carcinoma cell pyroptosis by targeting the miR-497/PELP1 axis

Cancer Letters, Journal Year: 2019, Volume and Issue: 450, P. 22 - 31

Published: Feb. 13, 2019

Language: Английский

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Single-cell transcriptional changes associated with drug tolerance and response to combination therapies in cancer

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: March 12, 2021

Tyrosine kinase inhibitors were found to be clinically effective for treatment of patients with certain subsets cancers carrying somatic mutations in receptor tyrosine kinases. However, the duration clinical response is often limited, and ultimately develop drug resistance. Here, we use single-cell RNA sequencing demonstrate existence multiple cancer cell subpopulations within lines, xenograft tumors patient tumors. These exhibit epigenetic changes differential therapeutic sensitivity. Recurrently overrepresented ontologies genes that are differentially expressed between tolerant populations sensitive cells include epithelial-to-mesenchymal transition, epithelium development, vesicle mediated transport, metabolism cholesterol homeostasis. We show analysis identified markers using LINCS database predict functionally validate small molecules target selected populations. In combination EGFR inhibitors, crizotinib inhibits emergence a defined subset inhibitor-tolerant clones. this study, describe spectrum associated tolerance inhibition specific agents.

Language: Английский

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Molecular Mechanisms of Acquired Resistance to MET Tyrosine Kinase Inhibitors in Patients with MET Exon 14–Mutant NSCLC

Clinical Cancer Research, Journal Year: 2020, Volume and Issue: 26(11), P. 2615 - 2625

Published: Feb. 7, 2020

Molecular mechanisms of acquired resistance to MET tyrosine kinase inhibitors (TKI) are poorly understood. We aimed characterize the genomic type I and II TKIs their impact on sequential TKI therapy outcomes in patients with metastatic exon 14-mutant NSCLC.Genomic alterations occurring at time progression were studied using plasma tissue next-generation sequencing (NGS).A total 20 had or available for analysis a TKI. Genomic known suspected be detected 15 (75%). On-target resistance, including single polyclonal domain mutations codons H1094, G1163, L1195, D1228, Y1230, high levels amplification allele, observed 7 (35%). A number off-target 9 (45%), KRAS amplifications KRAS, EGFR, HER3, BRAF; one case displayed both on- resistance. In 2 on-target resistant mutations, switching between resulted second partial responses.On-target secondary activation bypass signaling drive TKIs. deeper understanding these molecular can support development combinatorial therapeutic strategies overcome

Language: Английский

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