A reversible SRC-relayed COX2 inflammatory program drives resistance to BRAF and EGFR inhibition in BRAFV600E colorectal tumors DOI Creative Commons
Ana Ruiz-Sáenz, Chloé E. Atreya, Changjun Wang

et al.

Nature Cancer, Journal Year: 2023, Volume and Issue: unknown

Published: Feb. 9, 2023

Abstract BRAF V600E mutation confers a poor prognosis in metastatic colorectal cancer (CRC) despite combinatorial targeted therapies based on the latest understanding of signaling circuitry. To identify parallel resistance mechanisms induced by BRAF–MEK–EGFR co-targeting, we used high-throughput kinase activity mapping platform. Here show that SRC kinases are systematically activated CRC following inhibition ± EGFR and coordinated targeting with increases treatment efficacy vitro vivo. drives to therapy independently ERK inducing transcriptional reprogramming through β-catenin (CTNNB1). The EGFR-independent compensatory activation is mediated an autocrine prostaglandin E 2 loop can be blocked cyclooxygenase-2 (COX2) inhibitors. Co-targeting COX2 + promotes durable suppression tumor growth patient-derived xenograft models. represents drug-repurposing strategy overcome therapeutic CRC.

Language: Английский

Trends in kinase drug discovery: targets, indications and inhibitor design DOI
Misty M. Attwood, Doriano Fabbro, Aleksandr V. Sokolov

et al.

Nature Reviews Drug Discovery, Journal Year: 2021, Volume and Issue: 20(11), P. 839 - 861

Published: Aug. 5, 2021

Language: Английский

Citations

578
Optochemical Control of Biological Processes in Cells and Animals DOI
Nicholas Ankenbruck, Taylor M. Courtney,

Yuta Naro

et al.

Angewandte Chemie International Edition, Journal Year: 2017, Volume and Issue: 57(11), P. 2768 - 2798

Published: May 18, 2017

Biological processes are naturally regulated with high spatial and temporal control, as is perhaps most evident in metazoan embryogenesis. Chemical tools have been extensively utilized cell developmental biology to investigate cellular processes, conditional control methods expanded applications of these technologies toward resolving complex biological questions. Light represents an excellent external trigger since it can be controlled very precision. To this end, several optically developed applied living systems. In review we discuss recent developments optochemical tools, including small molecules, peptides, proteins, nucleic acids that irreversibly or reversibly through light irradiation, a focus on cells animals.

Language: Английский

Citations

388
Tissue-specific tumorigenesis: context matters DOI
Günter Schneider, Marc Schmidt‐Supprian, Roland Rad

et al.

Nature reviews. Cancer, Journal Year: 2017, Volume and Issue: 17(4), P. 239 - 253

Published: March 3, 2017

Language: Английский

Citations

264
Conformational states dynamically populated by a kinase determine its function DOI
Tao Xie, Tamjeed Saleh, P. Rossi

et al.

Science, Journal Year: 2020, Volume and Issue: 370(6513)

Published: Oct. 1, 2020

Protein kinases intrinsically sample a number of conformational states with distinct catalytic and binding activities. We used nuclear magnetic resonance spectroscopy to describe in atomic-level detail how Abl kinase interconverts between an active two discrete inactive structures. Extensive differences key structural elements the give rise multiple intrinsic regulatory mechanisms. The findings explain oncogenic mutants can counteract inhibitory mechanisms constitutively activate kinase. Energetic dissection revealed contributions activation loop, Asp-Phe-Gly (DFG) motif, spine, gatekeeper residue regulation. Characterization transient conformation which drug imatinib binds enabled elucidation drug-resistance Structural insight into highlights they be leveraged for design selective inhibitors.

Language: Английский

Citations

218
Glycosylation in cancer: Selected roles in tumour progression, immune modulation and metastasis DOI
Joana G. Rodrigues, Meritxell Balmaña, Joana A. Macedo

et al.

Cellular Immunology, Journal Year: 2018, Volume and Issue: 333, P. 46 - 57

Published: March 20, 2018

Language: Английский

Citations

193
The extracellular matrix as a key regulator of intracellular signalling networks DOI Open Access
Jordan F. Hastings, Joanna N. Skhinas, Dirk Fey

et al.

British Journal of Pharmacology, Journal Year: 2018, Volume and Issue: 176(1), P. 82 - 92

Published: March 6, 2018

The extracellular matrix (ECM) is a salient feature of all solid tissues within the body. This complex, acellular entity composed hundreds individual molecules whose assembly, architecture and biomechanical properties are critical to controlling behaviour phenotype different cell types residing tissues. Cells basic unit life core building block organs. At their simplest, they follow set rules, governed by genetic code effected through complex protein signalling networks that these genes encode. These assimilate process information received control cellular decisions govern fate. ECM biggest provider external stimuli cells as such responsible for influencing intracellular dynamics. In this review, we discuss inclusion central regulatory sub-network in computational models decision making, with focus on its role diseases cancer. LINKED ARTICLES: article part themed section Translating Matrix. To view other articles visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.1/issuetoc.

Language: Английский

Citations

191
Progress with covalent small-molecule kinase inhibitors DOI Creative Commons
Zheng Zhao, Philip E. Bourne

Drug Discovery Today, Journal Year: 2018, Volume and Issue: 23(3), P. 727 - 735

Published: Jan. 11, 2018

With reduced risk of toxicity and high selectivity, covalent small-molecule kinase inhibitors (CSKIs) have emerged rapidly. Through the lens structural system pharmacology, here we review this rapid progress by considering design strategies challenges opportunities offered current CSKIs.

Language: Английский

Citations

185
Coral: Clear and Customizable Visualization of Human Kinome Data DOI Creative Commons

Kathleen S. Metz,

Erika M. Deoudes,

Matthew E. Berginski

et al.

Cell Systems, Journal Year: 2018, Volume and Issue: 7(3), P. 347 - 350.e1

Published: Aug. 29, 2018

Language: Английский

Citations

166
Eph receptors and ephrins in cancer progression DOI
Elena B. Pasquale

Nature reviews. Cancer, Journal Year: 2023, Volume and Issue: 24(1), P. 5 - 27

Published: Nov. 23, 2023

Language: Английский

Citations

55
CRISPR/Cas9 systems: Delivery technologies and biomedical applications DOI Creative Commons

Yimin Du,

Yanfei Liu, Jiaxin Hu

et al.

Asian Journal of Pharmaceutical Sciences, Journal Year: 2023, Volume and Issue: 18(6), P. 100854 - 100854

Published: Oct. 21, 2023

The emergence of the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) genome-editing system has brought about a significant revolution in realm managing human diseases, establishing animal models, and so on. To fully harness potential this potent gene-editing tool, ensuring efficient secure delivery to target site is paramount. Consequently, developing effective methods for CRISPR/Cas9 become critical area research. In review, we present comprehensive outline strategies discuss their biomedical applications system. We also provide an in-depth analysis physical, viral vector, non-viral vector strategies, including plasmid-, mRNA- protein-based approach. addition, illustrate This review highlights key factors affecting process current challenges facing system, while delineating future directions prospects that could inspire innovative strategies. aims new insights ideas advancing CRISPR/Cas9-based facilitate breakthroughs research therapeutic applications.

Language: Английский

Citations

47