Dual Inhibition of KRASG12D and Pan-ERBB Is Synergistic in Pancreatic Ductal Adenocarcinoma DOI Creative Commons
Kevin Christian Montecillo Gulay, Xinlian Zhang, Vasiliki Pantazopoulou

и другие.

Cancer Research, Год журнала: 2023, Номер 83(18), С. 3001 - 3012

Опубликована: Июнь 28, 2023

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with low survival rate. Recently, new drugs that target KRASG12D, common mutation in PDAC, have been developed. We studied one of these compounds, MRTX1133, and found it was specific effective at nanomolar concentrations patient-derived organoid models cell lines harboring KRASG12D mutations. Treatment MRTX1133 upregulated the expression phosphorylation EGFR HER2, indicating inhibition ERBB signaling may potentiate antitumor activity. Indeed, irreversible pan-ERBB inhibitor, afatinib, potently synergized vitro, cells acquired resistance to vitro remained sensitive this combination therapy. Finally, afatinib led tumor regression longer orthotopic PDAC mouse models. These results suggest dual KRAS be synergistic circumvent rapid development patients mutant pancreatic cancer. Significance: KRAS-mutant models, including inhibitor–resistant show exquisite sensitivity combined targeting, which provides rationale for testing drug clinical trials.

Язык: Английский

Advances in covalent drug discovery DOI Open Access
Lydia Boike, Nathaniel J. Henning, Daniel K. Nomura

и другие.

Nature Reviews Drug Discovery, Год журнала: 2022, Номер 21(12), С. 881 - 898

Опубликована: Авг. 25, 2022

Язык: Английский

Процитировано

475
Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials DOI Creative Commons
Xin Xie, Tingting Yu,

Xiang Li

и другие.

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Сен. 6, 2023

Abstract Undruggable proteins are a class of that often characterized by large, complex structures or functions difficult to interfere with using conventional drug design strategies. Targeting such undruggable targets has been considered also great opportunity for treatment human diseases and attracted substantial efforts in the field medicine. Therefore, this review, we focus on recent development discovery targeting “undruggable” their application clinic. To make review well organized, discuss strategies proteins, including covalent regulation, allosteric inhibition, protein–protein/DNA interaction targeted nucleic acid-based approach, immunotherapy others.

Язык: Английский

Процитировано

154
Therapeutic developments in pancreatic cancer DOI
Zilun Hu, Eileen M. O’Reilly

Nature Reviews Gastroenterology & Hepatology, Год журнала: 2023, Номер 21(1), С. 7 - 24

Опубликована: Окт. 5, 2023

Язык: Английский

Процитировано

135
Endometriosis and adenomyosis: shared pathophysiology DOI Creative Commons
Serdar E. Bulun, Şule Yıldız, Mazhar Adli

и другие.

Fertility and Sterility, Год журнала: 2023, Номер 119(5), С. 746 - 750

Опубликована: Март 15, 2023

Язык: Английский

Процитировано

83
Adagrasib: First Approval DOI

Sohita Dhillon

Drugs, Год журнала: 2023, Номер 83(3), С. 275 - 285

Опубликована: Фев. 1, 2023

Язык: Английский

Процитировано

82
Insights for precision oncology from the integration of genomic and clinical data of 13,880 tumors from the 100,000 Genomes Cancer Programme DOI Creative Commons
Alona Sosinsky,

John C. Ambrose,

William Cross

и другие.

Nature Medicine, Год журнала: 2024, Номер 30(1), С. 279 - 289

Опубликована: Янв. 1, 2024

Abstract The Cancer Programme of the 100,000 Genomes Project was an initiative to provide whole-genome sequencing (WGS) for patients with cancer, evaluating opportunities precision cancer care within UK National Healthcare System (NHS). Genomics England, alongside NHS analyzed WGS data from 13,880 solid tumors spanning 33 types, integrating genomic real-world treatment and outcome data, a secure Research Environment. Incidence somatic mutations in genes recommended standard-of-care testing varied across types. For instance, glioblastoma multiforme, small variants were present 94% cases copy number aberrations at least one gene 58% cases, while sarcoma demonstrated highest occurrence actionable structural (13%). Homologous recombination deficiency identified 40% high-grade serous ovarian 30% linked pathogenic germline variants, highlighting value combined analysis. linkage longitudinal life course clinical allowed assessment outcomes stratified according pangenomic markers. Our findings demonstrate utility linking enable survival analysis identify that affect prognosis advance our understanding how genomics impacts patient outcomes.

Язык: Английский

Процитировано

81
Expanding PROTACtable genome universe of E3 ligases DOI Creative Commons
Yuan Liu, Jingwen Yang, Tianlu Wang

и другие.

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Окт. 16, 2023

Abstract Proteolysis-targeting chimera (PROTAC) and other targeted protein degradation (TPD) molecules that induce by the ubiquitin-proteasome system (UPS) offer new opportunities to engage targets remain challenging be inhibited conventional small molecules. One fundamental element in process is E3 ligase. However, less than 2% amongst hundreds of ligases human genome have been engaged current studies TPD field, calling for recruiting additional ones further enhance therapeutic potential TPD. To accelerate development PROTACs utilizing under-explored ligases, we systematically characterize from seven different aspects, including chemical ligandability, expression patterns, protein-protein interactions (PPI), structure availability, functional essentiality, cellular location, PPI interface analyzing 30 large-scale data sets. Our analysis uncovers several as promising extant PROTACs. In total, combining confidence score, pattern, PPI, identified 76 PROTAC-interacting candidates. We develop a user-friendly flexible web portal ( https://hanlaboratory.com/E3Atlas/ ) aimed at assisting researchers rapidly identify with activities against specifically desired targets, facilitating these therapies cancer beyond.

Язык: Английский

Процитировано

72
Treatment Strategies for KRAS-Mutated Non-Small-Cell Lung Cancer DOI Open Access
E O'Sullivan, Anna Keogh,

Brian E. Henderson

и другие.

Cancers, Год журнала: 2023, Номер 15(6), С. 1635 - 1635

Опубликована: Март 7, 2023

Activating mutations in KRAS are highly prevalent solid tumours and frequently found 35% of lung, 45% colorectal, up to 90% pancreatic cancers. Mutated is a prognostic factor for disease-free survival (DFS) overall (OS) NSCLC associated with more aggressive clinical phenotype, highlighting the need KRAS-targeted therapy. Once considered undruggable due its smooth shallow surface, breakthrough showed that activated G12C-mutated isozyme can be directly inhibited via newly identified switch II pocket. This discovery led development new class selective small-molecule inhibitors against G12C isoform. Sotorasib adagrasib approved locally advanced or metastatic patients who have received at least one prior systemic Currently, there twelve being tested trials, either as single agent combination. In this study, mutation prevalence, subtypes, rates occurrence treatment-resistant invasive mucinous adenocarcinomas (IMAs), novel drug delivery options reviewed. Additionally, current status inhibitors, multiple resistance mechanisms limit efficacy, their use combination treatment strategies multitargeted approaches discussed.

Язык: Английский

Процитировано

46
Epigallocatechin-3-Gallate Therapeutic Potential in Cancer: Mechanism of Action and Clinical Implications DOI Creative Commons
Mateusz Kciuk, Manzar Alam, Nemat Ali

и другие.

Molecules, Год журнала: 2023, Номер 28(13), С. 5246 - 5246

Опубликована: Июль 6, 2023

Cellular signaling pathways involved in the maintenance of equilibrium between cell proliferation and apoptosis have emerged as rational targets that can be exploited prevention treatment cancer. Epigallocatechin-3-gallate (EGCG) is most abundant phenolic compound found green tea. It has been shown to regulate multiple crucial cellular pathways, including those mediated by EGFR, JAK-STAT, MAPKs, NF-κB, PI3K-AKT-mTOR, others. Deregulation abovementioned pathophysiology demonstrated EGCG may exert anti-proliferative, anti-inflammatory, apoptosis-inducing effects or induce epigenetic changes. Furthermore, preclinical clinical studies suggest used numerous disorders, This review aims summarize existing knowledge regarding biological properties EGCG, especially context cancer prophylaxis.

Язык: Английский

Процитировано

41
Targeting cancer with small-molecule pan-KRAS degraders DOI
Johannes Popow, William Farnaby, Andreas Gollner

и другие.

Science, Год журнала: 2024, Номер 385(6715), С. 1338 - 1347

Опубликована: Сен. 19, 2024

Mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) protein are highly prevalent cancer. However, small-molecule concepts that address oncogenic KRAS alleles remain elusive beyond replacing glycine at position 12 with cysteine (G12C), which is clinically drugged through covalent inhibitors. Guided by biophysical and structural studies of ternary complexes, we designed a heterobifunctional small molecule potently degrades 13 out 17 most alleles. Compared inhibition, degradation results more profound sustained pathway modulation across broad range mutant cell lines, killing cancer cells while sparing models without genetic aberrations. Pharmacological was tolerated led to tumor regression vivo. Together, these findings unveil new path toward addressing KRAS-driven cancers degraders.

Язык: Английский

Процитировано

33