Role of phosphoproteomics in the development of personalized cancer therapies

Abstract

Cell signalling pathways driven by protein and lipid kinases contribute to the onset and progression of virtually all cancer types. Consequently, several inhibitors against these enzymes have clinical utility for the treatment of different forms of cancer. A problem that hampers further development is that not all patients respond equally well to kinase inhibitors and a significant proportion of those that initially respond eventually develop resistance. This review considers how an integrative analysis of kinase signalling may be used to address this issue. Advances in the biophysics of mass spectrometry, in biochemical procedures for phosphopeptide enrichment, and in computational approaches for label-free quantification have contributed to the development of phosphoproteomics workflows compatible with the analysis of clinical material. These developments, together with new bioinformatics tools to derive information on signalling circuitry from phosphoproteomics data, allow investigating kinase networks with unprecedented depth. Phosphoproteomics technology is starting to be used in translational research and, with further developments, such methods may also be able to measure the circuitry of cancer signalling networks in routine clinical assays. This review reflects on how this information could be used to accurately predict the best kinase inhibitor for each individual cancer patient.

Phosphotyrosine-based-phosphoproteomics scaled-down to biopsy level for analysis of individual tumor biology and treatment selection

“…Based on its potential to provide insight in tumor signaling pathways and potential drug targets, MS-based quantitative phosphoproteomics of tumor tissues has been suggested as a method for selection of protein kinase inhibitors in individual patients with cancer [12,20,21]. To enable clinical implementation of this approach for personalized medicine the phosphoproteomics workflows should be compatible with clinically available sample amounts such as needle biopsies and reproducible.…”

“…Drawbacks of this approach are the limited number of phosphosite-specific antibodies targeting assumed epitopes of interest [20,38]. In contrast, the 'unbiased' analysis of the signaling network by MS-based phosphoproteomics we used here may benefit the development of personalized therapies [12]. …”

“…Proven reproducible and reliable with advancing technology, MS-based quantitative phosphoproteomics of patient tumor tissues has been suggested as a method for selection of protein kinase inhibitors in individual patients [12,20,21]. Importantly, single shot nanoLC- [17,22,23], the current pTyrphosphoproteomics workflow requires protein input of typically 10-20 mg per sample, corresponding to about 100-200 mg tissue wet weight [14].…”

“…Mass spectrometry-based phosphoproteomics provides insight in these tumor-promoting signaling pathways and potential drug targets through global analysis of phosphorylated proteins [12,13]. As phosphotyrosines represent only 1-2% of the cellular…”

An 80-gene set to predict response to preoperative chemoradiotherapy for rectal cancer by principle component analysis

“…In rectal cancers of the same pathological differentiation, alternative splicing of a gene may lead to different resistances to various treatments, including CRT. Haley et al and Cutillas et al reported that phosphoproteomics enabled tumor cells to survive against chemotherapeutics (27,28). However, the septin complex was the major annotated function among Figure 3.…”