Dataset Information

Illuminating phenotypic drug responses of sarcoma cells to kinase inhibitors by phosphoproteomics

ABSTRACT: Kinase inhibitors (KIs) are important cancer drugs but often display polypharmacology that is molecularly not understood. This disconnect is particularly apparent in cancer entities such as sarcomas for which the oncogenic drivers are often not clear. To investigate more systematically how the cellular proteotypes of sarcoma cells shape their response to molecularly targeted drugs, we profiled the proteomes and phosphoproteomes of 17 sarcoma cell lines and screened the same cells against 150 cancer drugs. The resulting 2,550 phenotypic drug profiles revealed distinct drug responses and the cellular activity landscapes derived from deep (phospho)proteomes (9-10,000 proteins and 10-27,000 phosphorylation sites per cell line) enabled several lines of analysis. For instance, connecting the (phospho)proteomic data with drug responses revealed known and novel mechanisms of action (MoAs) of kinase inhibitors and identified markers of drug sensitivity or resistance. All data is publically accessible via an interactive web application that enables exploration of this rich molecular resource for better understanding active signalling pathways in sarcoma cells, identifying treatment response predictors, and revealing novel MoA of clinical KIs.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Bernhard Kuster

PROVIDER: MSV000091043 | MassIVE | Wed Jan 11 07:52:00 GMT 2023

SECONDARY ACCESSION(S): PXD039363

REPOSITORIES: MassIVE

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Illuminating phenotypic drug responses of sarcoma cells to kinase inhibitors by phosphoproteomics.

Lee Chien-Yun CY The Matthew M Meng Chen C Bayer Florian P FP Putzker Kerstin K Müller Julian J Streubel Johanna J Woortman Julia J Sakhteman Amirhossein A Resch Moritz M Schneider Annika A Wilhelm Stephanie S Kuster Bernhard B

Molecular systems biology 20231218 1

Kinase inhibitors (KIs) are important cancer drugs but often feature polypharmacology that is molecularly not understood. This disconnect is particularly apparent in cancer entities such as sarcomas for which the oncogenic drivers are often not clear. To investigate more systematically how the cellular proteotypes of sarcoma cells shape their response to molecularly targeted drugs, we profiled the proteomes and phosphoproteomes of 17 sarcoma cell lines and screened the same against 150 cancer dr ...[more]

PMID: 38177929

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Project description:In this study the investigators looked at adaptive reprogramming impact on the kinome when a MEK inhibitor called GSK1120212 (trametinib) was administered in a "window of opportunity" trial. GSK1120212 is not yet approved by the FDA for use in breast cancer patients. The investigators gave GSK1120212 for a short period of time (one week) to examine MEK and the other kinase expression in cancer cells both before and after the study drug is given. The investigators gave this drug for research purposes only. The length of time it was given is not intended to treat cancer. Recently researchers at UNC developed a process that can comprehensively profile the majority of the individual kinases in the kinome and examine the impact on kinase expression of kinase inhibitors (Duncan et al, Cell 2012, PMID: 22500798). This can tell us which kinases need to be concurrently blocked to augment responsiveness and prevent acquired resistance so that the investigators can design the best combinations of kinase blocking drugs for triple negative breast cancer. This is especially important for individuals with triple negative breast cancer (TNBC) because there are no targeted drugs available that can block molecules that affect tumor growth. The investigators believe that kinase-blocking drugs have the potential to be a more effective treatment for people with TNBC. In this recently published study (Zawistowski et al, Cancer Discovery 2017, PMID: 28108460), TNBC patients treated with trametinib for 7 days resulted in a transcriptional response characterized by significant reprogramming of the tyrosine kinome, and this adaptive bypass response in human tumors was found to be similar to that seen in preclinical models including TNBC cell lines and mouse xenografts. In this study we also examined whether reprogramming differed between TNBC molecular subtypes, finding that basal-like and claudin-low human TNBC cells and mouse tumor subtypes had different adaptive transcriptional responses to MEK-ERK inhibition. Mechanistically we found that genome-wide enhancer remodeling drove the adaptive transcriptional response, suggesting that epigenetic approaches to reprogramming may be more durable than kinase inhibitor polypharmacology.