Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer

Cancers, Journal Year: 2021, Volume and Issue: 13(11), P. 2666 - 2666

Published: May 28, 2021

Drug resistance is perhaps the greatest challenge in improving outcomes for cancer patients undergoing treatment with targeted therapies. It becoming clear that “persisters,” a subpopulation of drug-tolerant cells found populations, play critical role development drug resistance. Persisters are able to maintain viability under therapy but typically slow cycling or dormant. These do not harbor classic driver alterations, and their partial phenotype transient reversible upon removal drug. In clinic, persister state most closely corresponds minimal residual disease from which relapse can occur if discontinued acquired develops response continuous therapy. Thus, eliminating will be crucial improve patients. Using lung therapies as primary paradigm, this review give an overview characteristics cells, mechanisms associated tolerance, potential therapeutic opportunities target cell population tumors.

Language: Английский

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Hippo signalling in the liver: role in development, regeneration and disease

Nature Reviews Gastroenterology & Hepatology, Journal Year: 2022, Volume and Issue: 19(5), P. 297 - 312

Published: Jan. 21, 2022

Language: Английский

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Binary pan-cancer classes with distinct vulnerabilities defined by pro- or anti-cancer YAP/TEAD activity

Cancer Cell, Journal Year: 2021, Volume and Issue: 39(8), P. 1115 - 1134.e12

Published: July 21, 2021

Language: Английский

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Mechanism of Drug Tolerant Persister Cancer Cells: The Landscape and Clinical Implication for Therapy

Journal of Thoracic Oncology, Journal Year: 2021, Volume and Issue: 16(11), P. 1798 - 1809

Published: Aug. 3, 2021

Language: Английский

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Insights into recent findings and clinical application of YAP and TAZ in cancer

Nature reviews. Cancer, Journal Year: 2023, Volume and Issue: 23(8), P. 512 - 525

Published: June 12, 2023

Language: Английский

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Small extracellular vesicles in combination with sleep-related circRNA3503: A targeted therapeutic agent with injectable thermosensitive hydrogel to prevent osteoarthritis

Bioactive Materials, Journal Year: 2021, Volume and Issue: 6(12), P. 4455 - 4469

Published: May 6, 2021

Osteoarthritis (OA), characterized by chondrocyte apoptosis and disturbance of the balance between catabolism anabolism extracellular matrix (ECM), is most common age-related degenerative joint disease worldwide. As sleep has been found to be beneficial for cartilage repair, circular RNAs (circRNAs) have demonstrated involved in pathogenesis OA, we performed RNA sequencing (RNA-seq), circRNA3503 was significantly increased after melatonin (MT)-induced cell sleep. Upregulation expression completely rescued effects interleukin-1β (IL-1β), which used simulate on apoptosis, ECM degradation- synthesis-related genes. Mechanistically, acted as a sponge hsa-miR-181c-3p hsa-let-7b-3p. Moreover, previously showed that small vesicles (sEVs) derived from synovium mesenchymal stem cells (SMSCs) can not only successfully deliver nucleic acids chondrocytes, but also effectively promote proliferation migration, assessed feasibility sEVs combination with sleep-related an OA therapy. We produced isolated circRNA3503-loaded (circRNA3503-OE-sEVs) SMSCs. Then, poly(D,l-lactide)-b-poly(ethylene glycol)-b-poly(D,l-lactide) (PDLLA-PEG-PDLLA, PLEL) triblock copolymer gels were carriers sEVs. Through vivo vitro experiments, PLEL@circRNA3503-OE-sEVs shown highly-effective therapeutic strategy prevent progression. multiple pathways, circRNA3503-OE-sEVs alleviated inflammation-induced imbalance synthesis degradation acting In addition, promoted renewal alleviate progressive loss chondrocytes. Our results highlight potential preventing

Language: Английский

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An allosteric pan-TEAD inhibitor blocks oncogenic YAP/TAZ signaling and overcomes KRAS G12C inhibitor resistance

Nature Cancer, Journal Year: 2023, Volume and Issue: 4(6), P. 812 - 828

Published: June 5, 2023

Abstract The Hippo pathway is a key growth control that conserved across species. downstream effectors of the pathway, YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif), are frequently activated in cancers to drive proliferation survival. Based on premise sustained interactions between YAP/TAZ TEADs enhanced associate domain) central their transcriptional activities, we discovered potent small-molecule inhibitor (SMI), GNE-7883, allosterically blocks all human TEAD paralogs through binding lipid pocket. GNE-7883 effectively reduces chromatin accessibility specifically at motifs, suppresses cell variety line models achieves strong antitumor efficacy vivo. Furthermore, uncovered overcomes both intrinsic acquired resistance KRAS (Kirsten rat sarcoma viral oncogene homolog) G12C inhibitors diverse preclinical inhibition activation. Taken together, this work demonstrates activities SMIs YAP/TAZ-dependent highlights potential broad applications precision oncology therapy resistance.

Language: Английский

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Therapeutic targeting of TEAD transcription factors in cancer

Trends in Biochemical Sciences, Journal Year: 2023, Volume and Issue: 48(5), P. 450 - 462

Published: Jan. 26, 2023

Language: Английский

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Poziotinib for EGFR exon 20-mutant NSCLC: Clinical efficacy, resistance mechanisms, and impact of insertion location on drug sensitivity

Cancer Cell, Journal Year: 2022, Volume and Issue: 40(7), P. 754 - 767.e6

Published: July 1, 2022

We report a phase II study of 50 advanced non-small cell lung cancer (NSCLC) patients with point mutations or insertions in EGFR exon 20 treated poziotinib (NCT03066206). The achieved its primary endpoint, confirmed objective response rates (ORRs) 32% and 31% by investigator blinded independent review, respectively, median progression-free survival 5.5 months. Using preclinical studies, silico modeling, molecular dynamics simulations, we found that sensitivity was highly dependent on the insertion location, near-loop (amino acids A767 to P772) being more sensitive than far-loop insertions, an observation clinically ORRs 46% 0% observed near versus far-loop, respectively (p = 0.0015). Putative mechanisms acquired resistance included T790M, MET amplifications, epithelial-to-mesenchymal transition (EMT). Our data demonstrate is active 20-mutant NSCLC, although this activity influenced location.

Language: Английский

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Pharmacological blockade of TEAD–YAP reveals its therapeutic limitation in cancer cells

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Nov. 8, 2022

Abstract Targeting TEAD autopalmitoylation has been proposed as a therapeutic approach for YAP-dependent cancers. Here we show that palmitoylation inhibitor MGH-CP1 and analogues block cancer cell “stemness”, organ overgrowth tumor initiation in vitro vivo. sensitivity correlates significantly with YAP-dependency large panel of lines. However, inhibition or YAP/TAZ knockdown leads to transient cycle progression without inducing death, undermining their potential utilities. We further reveal silencing VGLL3-mediated transcriptional activation SOX4/PI3K/AKT signaling axis, which contributes survival confers resistance inhibitors. Consistently, combination AKT inhibitors exhibits strong synergy death. Our work characterizes the opportunities limitations cancers, uncovers an intrinsic molecular mechanism, resistance.

Language: Английский

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