Impact of phosphoproteomics in the translation of kinase‐targeted therapies

Abstract

Signaling pathways driven by protein and lipid kinases are altered in most human diseases. Therefore, pharmacological inhibitors of cell signaling are one of the most intensively pursued therapeutic approaches for the treatment of diseases such as cancer, neurodegeneration, and metabolic syndromes. Phosphoproteomics is a technique that measures the products of kinase activities and, with the appropriate bioinformatics techniques, the methodology can also provide measures of kinase pathway activation and network circuitry. Hence, due to recent technological advantages, LC-MS-based quantitative phosphoproteomics provides relevant information for the design and implementation of kinase inhibitor based therapies. Here, we review how phosphoproteome profiling is being used in translational research as a means to identify drug targets and biomarkers for personalizing therapies based on kinase inhibitors.

INKA , an integrative data analysis pipeline for phosphoproteomic inference of active kinases

“…This complexity calls for tailored therapy based on detailed knowledge of the individual tumor's biology, including a comprehensive profile of hyperactive kinases. MS‐based phosphoproteomics enables global protein phosphorylation profiling of cells and tissues (Jimenez & Verheul, ; Casado et al , ), but to arrive at a prioritized list of actionable (combinations of) active kinases, a dedicated analysis pipeline is required as the data are massive and complex. Importantly, a prime prerequisite for personalized treatment requires that the analysis is based on a single sample.…”

Proteasome inhibitor-induced modulation reveals the spliceosome as a specific therapeutic vulnerability in multiple myeloma

“…We chose timepoints across 24 h for analysis based on our prior results demonstrating how the proteomic response to PI evolves over many hours 9 . This is in contrast with most phosphoproteomic studies, examining direct kinase effects on a timescale of minutes 14 . Here we instead consider the indirect effects on phosphorylation induced by PI exposure.…”

“…We hypothesized that additional modalities of response, and thereby new myeloma-relevant therapeutic targets, may be revealed by studying the signaling-level response to PIs with unbiased mass spectrometry-based phosphoproteomics. The large majority of therapy-relevant investigations using this technique have focused on elucidating the effects of kinase inhibitors 14 . However, we reasoned that a significant cellular perturbation such as proteasome inhibition would likely also indirectly perturb kinase and phosphatase signaling in a broad fashion.…”

Approaches to identify kinase dependencies in cancer signalling networks

“…Thus, although targeting aberrant kinase activity in oncology remains an attractive therapeutic option, the success of such therapies requires identifying kinase dependencies in cancer cells and biomarkers of sensitivity so that oncologists are able to select the correct inhibitor for each patient . Current approaches to stratify patients for therapy are based on the analysis of genetic mutations, which provide proxies of pathway activation, but it has been argued that more precise companion diagnostic approaches will require the ability to quantify kinase activity more directly .…”