Protein degradation: expanding the toolbox to restrain cancer drug resistance

Journal of Hematology & Oncology, Год журнала: 2023, Номер 16(1)

Опубликована: Янв. 24, 2023

Abstract Despite significant progress in clinical management, drug resistance remains a major obstacle. Recent research based on protein degradation to restrain has attracted wide attention, and several therapeutic strategies such as inhibition of proteasome with bortezomib proteolysis-targeting chimeric have been developed. Compared intervention at the transcriptional level, targeting process seems be more rapid direct strategy. Proteasomal proteolysis lysosomal are most critical quality control systems responsible for proteins or organelles. Although proteasomal inhibitors (e.g., chloroquine) achieved certain improvements some application scenarios, their routine practice is still long way off, which due lack precise capabilities inevitable side effects. In-depth studies regulatory mechanism regulators, including E3 ubiquitin ligases, deubiquitylating enzymes (DUBs), chaperones, expected provide clues developing reducing Here, we discuss underlying mechanisms regulating efflux, metabolism, DNA repair, target alteration, downstream bypass signaling, sustaining stemness, tumor microenvironment remodeling delineate functional roles resistance. We also highlight specific DUBs, discussing possible modulating cancer A systematic summary molecular basis by regulates will help facilitate development appropriate strategies.

Язык: Английский

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Targeted therapies for KRAS-mutant non-small cell lung cancer: from preclinical studies to clinical development—a narrative review

Translational Lung Cancer Research, Год журнала: 2023, Номер 12(2), С. 346 - 368

Опубликована: Фев. 1, 2023

Background and Objective: Non-small cell lung cancer (NSCLC) with Kirsten rat sarcoma viral oncogene homolog (KRAS) driver alterations harbors a poor prognosis standard therapies, including chemotherapy and/or immunotherapy anti-programmed death protein 1 (anti-PD-1) or ligand-1 (anti-PD-L1) antibodies. Selective KRAS G12C inhibitors have been shown to provide significant clinical benefit in pretreated NSCLC patients mutation. Methods: In this review, we describe the biology of KRAS-mutant tumors review data from preclinical studies trials on KRAS-targeted therapies Key Content Findings: is most frequently mutated human cancer. The common mutation found NSCLC. Sotorasib first, selective inhibitor receive approval based demonstration tolerable safety profile previously treated, G12C-mutated Adagrasib, highly covalent G12C, has also efficacy other novel are being under evaluation early-phase studies. Similarly oncogene-directed mechanisms intrinsic acquired resistance limiting activity these agents described. Conclusions: discovery changed therapeutic scenario G12C-mutant Various testing different settings disease, as single-agent combination targeted for synthetic lethality immunotherapy, currently ongoing molecularly-defined subgroup further improve outcomes.

Язык: Английский

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A prime editor mouse to model a broad spectrum of somatic mutations in vivo

Nature Biotechnology, Год журнала: 2023, Номер unknown

Опубликована: Май 11, 2023

Язык: Английский

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Mutant KRAS Mediates circARFGEF2 Biogenesis to Promote Lymphatic Metastasis of Pancreatic Ductal Adenocarcinoma

Cancer Research, Год журнала: 2023, Номер 83(18), С. 3077 - 3094

Опубликована: Июнь 26, 2023

Circular RNAs (circRNA) contribute to cancer stemness, proliferation, and metastasis. The biogenesis of circRNAs can be impacted by the genetic landscape tumors. Herein, we identified a novel circRNA, circARFGEF2 (hsa_circ_0060665), which was upregulated in KRASG12D pancreatic ductal adenocarcinoma (PDAC) positively associated with PDAC lymph node (LN) CircARFGEF2 overexpression significantly facilitated LN metastasis vitro vivo. Mechanistically, activated alternative splicing factor QKI-5, recruited U2AF35 facilitate spliceosome assembly. QKI-5 bound QKI binding motifs neighboring reverse complement sequence intron 3 6 ARFGEF2 pre-mRNA biogenesis. sponged miR-1205 promoted activation JAK2, phosphorylated STAT3 trigger lymphangiogenesis Importantly, silencing inhibited KrasG12D/+Trp53R172H/+Pdx-1-Cre (KPC) mouse model. These findings provide insight into mechanism metastasis-promoting function mutant KRAS-mediated circRNA

Язык: Английский

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Experimental mouse models for translational human cancer research

Frontiers in Immunology, Год журнала: 2023, Номер 14

Опубликована: Март 10, 2023

The development and growth of tumors remains an important ongoing threat to human life around the world. While advanced therapeutic strategies such as immune checkpoint therapy CAR-T have achieved astonishing progress in treatment both solid hematological malignancies, malignant initiation progression cancer a controversial issue, further research is urgently required. experimental animal model not only has great advantages simulating occurrence, development, transformation mechanisms tumors, but also can be used evaluate effects diverse array clinical interventions, gradually becoming indispensable method for research. In this paper, we reviewed recent relation mouse rat models, focusing on spontaneous, induced, transgenic, transplantable tumor help guide future study prevention.

Язык: Английский

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