Dataset Information

Highly multiplexed kinase profiling in spleen with targeted mass spectrometry reveals kinome plasticity across species

ABSTRACT: Early attrition of drug candidates, including kinase inhibitors, often occurs due to issues that arise during preclinical safety and efficacy evaluation. This problem may be exacerbated by the fact that these studies might fail to consider the basic physiological differences which could exist between human patients and animal models. Little is currently known about how kinase expression can vary between species, and tools to quantitatively measure such differences are lacking. We report the development of a targeted mass spectrometry-based assay capable of monitoring >50 different kinases using peptides conserved in humans and the key preclinical species used in drug development (mouse, rat, dog and cynomolgus monkey). These methods were then used to profile inter-species kinome variability in spleen with three of the current techniques used in targeted proteomics (MRM, PRM and IS-PRM). IS-PRM provided the highest number of kinase identifications, and the results indicate that while this initial set of kinases exhibits high correlation between species for this tissue type, discreet species-specific differences do exist, especially within the cyclin-dependent kinase (CDK) family. Understanding these differences could help rationalize the findings of preclinical studies and have major implications for the selection of these animals as models in kinase drug development.

ORGANISM(S): Homo Sapiens Rattus Norvegicus Mus Musculus Canis Lupus Familiaris Macaca Fascicularis

SUBMITTER: Laura Marholz

PROVIDER: PXD024650 | panorama | Thu Aug 19 00:00:00 BST 2021

REPOSITORIES: PanoramaPublic

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Publications

Highly Multiplexed Kinase Profiling in Spleen with Targeted Mass Spectrometry Reveals Kinome Plasticity across Species.

Marholz Laura J LJ Federspiel Joel D JD Suh Hyunsuk H Fernandez Ocana Mireia M

Journal of proteome research 20210728 9

Early attrition of drug candidates, including kinase inhibitors, often occurs due to issues that arise during preclinical safety and efficacy evaluation. This problem may be exacerbated by the fact that these studies might fail to consider the basic physiological differences that could exist between human patients and animal models. We report the development of a targeted mass spectrometry-based assay capable of monitoring >50 different kinases using peptides conserved in humans and the key prec ...[more]

PMID: 34319750

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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.

Dataset Information

Highly multiplexed kinase profiling in spleen with targeted mass spectrometry reveals kinome plasticity across species

Publications

Highly Multiplexed Kinase Profiling in Spleen with Targeted Mass Spectrometry Reveals Kinome Plasticity across Species.

Similar Datasets

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