AI Article Synopsis
- Researchers are developing covalent inhibitors targeting the KRAS oncoprotein and testing them in clinical trials, but resistance to these treatments can limit their long-term effectiveness.
- By utilizing mass-spectrometry-based quantitative temporal proteomics, they profiled the response to KRAS inhibitors in various cancer cell models, identifying over 10,000 proteins involved.
- The study found that combining KRAS inhibitors with other drugs like PI3K and HSP90 inhibitors can shift treatment responses from being merely halting (cytostatic) to actively killing cancer cells (cytotoxic), suggesting effective treatment strategies against resistant tumors.
Article Abstract
Covalent inhibitors of the KRAS oncoprotein have recently been developed and are being evaluated in clinical trials. Resistance to targeted therapies is common and may limit long-term efficacy of KRAS inhibitors (KRASi). To identify pathways of adaptation to KRASi and predict drug combinations that circumvent resistance, we use mass-spectrometry-based quantitative temporal proteomics to profile the proteomic response to KRASi in pancreatic and lung cancer 2D and 3D cellular models. We quantify 10,805 proteins, representing the most comprehensive KRASi proteome (https://manciaslab.shinyapps.io/KRASi/). Our data reveal common mechanisms of acute and long-term response between KRAS-driven tumors. Based on these proteomic data, we identify potent combinations of KRASi with phosphatidylinositol 3-kinase (PI3K), HSP90, CDK4/6, and SHP2 inhibitors, in some instances converting a cytostatic response to KRASi monotherapy to a cytotoxic response to combination treatment. Overall, using quantitative temporal proteomics, we comprehensively characterize adaptations to KRASi and identify combinatorial regimens with potential therapeutic utility.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.celrep.2020.03.021 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Deciphering the Energy Transfer Mechanism Across Metal Halide Perovskite-Phthalocyanine Interfaces.
Adv Sci (Weinh)
January 2025
Institute of Molecular Science, University of Valencia, c/Catedrático José Beltrán Martínez 2, Paterna, 46980, Valencia, Spain.
Energy transfer processes in nanohybrids are at the focal point of conceptualizing, designing, and realizing novel energy-harvesting systems featuring nanocrystals that absorb photons and transfer their energy unidirectionally to surface-immobilized functional dyes. Importantly, the functionality of these dyes defines the ultimate application. Herein, CsPbBr perovskite nanocrystals (NCs) are interfaced with zinc phthalocyanine (ZnPc) dyes featuring carboxylic acid.
View Article and Find Full Text PDFInnovation and diversity in public health team engagement in local alcohol premises licensing: qualitative interview findings from the ExILEnS study.
Public Health Res (Southampt)
January 2025
Institute for Social Marketing and Health, University of Stirling, Stirling, Scotland, UK.
Background: Evidence suggests that controls on the physical and temporal availability of alcohol can reduce alcohol-related harms. Public health teams in England and Scotland have in recent years been given a statutory role in licensing systems through which premises are granted permits to sell alcohol. The Exploring the Impact of alcohol premises Licensing in England and Scotland study examined public health team efforts to engage in alcohol licensing from 2012 to 2019.
View Article and Find Full Text PDFCurrent Trends, Spatio-Temporal Dynamics of Microplastics Research and Global Public Health: A Scientometric Study.
Health Sci Rep
January 2025
Vicerrectorado de Investigación Universidad San Ignacio de Loyola Lima Peru.
Purpose: To evaluate the current trends and spatiotemporal dynamics of microplastic research and public health through a scientometric study from 2019 to 2024.
Methods: An observational and descriptive approach was applied to the published literature on microplastics and public health published in January 2019 and July 2024. A quantitative approach was used to analyze document production, author-country collaborations and thematic evolution.
Changes of the ecological environment status in villages under the background of traditional village preservation: a case study in Enshi Tujia and Miao Autonomous Prefecture.
Sci Rep
January 2025
Faculty of Resources and Environmental Science, Hubei University, Wuhan, China.
The preservation of Chinese traditional villages plays a crucial role in promoting the sustainable development of rural natural, cultural, and ecological environments. It is also a key strategy for achieving rural revitalization. Current research on traditional villages predominantly focuses on the realm of cultural landscapes, with an emphasis on preserving the cultural ecological value of these communities.
View Article and Find Full Text PDFSTIPS algorithm enables tracking labyrinthine patterns and reveals distinct rhythmic dynamics of actin microridges.
Phys Biol
January 2025
Department of Biological Sciences, Tata Institute of Fundamental Research Department of Biological Sciences, Tata Institute of Fundamental Research, Homi Bhabha road, Navy Nagar, Colaba, Mumbai-400005, INDIA, Mumbai, 400005, INDIA.
Tracking and motion analyses of semi-flexible biopolymer networks from time-lapse microscopy images are important tools that enable quantitative measurements to unravel the dynamic and mechanical properties of biopolymers in living tissues, crucial for understanding their organization and function. Biopolymer networks are challenging to track due to continuous stochastic transitions, such as merges and splits, which cause local neighbourhood rearrangements over short time and length scales. To address this, we propose the STIPS algorithm (Spatio Temporal Information on Pixel Subsets) to track these events by creating pixel subsets that link trajectories across frames.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!