Abstract 4808: Discovery of a phospho-signature predicting response to dasatinib in non-small cell lung cancer

Abstract

Since targeted drugs selectively block molecular pathways that are typically over-activated in tumour cells, they are more precise and show fewer adverse effects than traditional chemotherapeutic agents. At the same time the proportion of patients that benefit from targeted drugs is smaller. Therefore, predictive molecular markers are needed to confidently predict the patient's response to a specific therapy. Such markers would facilitate therapy personalization, where the selected therapy is based on the molecular profile of the patient. We sought to identify a signature of protein phosphorylations that predicts the response to dasatinb in non-small cell lung cancer cell lines. A panel of cell lines were profiled in a global, unbiased, phosphoproteomics study yielding quantitative information for roughly 25,000 phosphorylation sites. The identical cell lines were tested for their response to dasatinib. From the phosphoproteome profiles, we identified a signature of twelve phosphorylation sites that can accurately predict dasatinib sensitivity. Four of the phosphorylation sites belong to integrin α4, a protein that mediates cell-matrix or cell-cell adhesion. We evaluated the performance of this signature in a cross-validation set-up and investigated the robustness of the selected predictive features. Finally, we confirmed the predictive power of the signature in an independent set of breast cancer cell lines. We showed that the phosphorylations of integrin β4 as well as eight further proteins are candidate biomarkers for predicting response to dasatinib in solid tumours. Furthermore, we demonstrated that identifying predictive phosphorylation signatures from global, quantitative phosphoproteomic data is possible, and opens a new path to discovering molecular markers for response prediction. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4808. doi:1538-7445.AM2012-4808

The emerging field of chemo‐ and pharmacoproteomics

“…Furthermore, to gain insights in cellular regulation global effects of drugs on post-translational modifications (e.g. phosphorylation, ubiquitinylation, acetylation, glycosylation) are regularly studied [52][53][54][55][56][57][58][59][60].…”

“…A number of successful studies focused on a specific post-translational modification. For instance, phosphorylation studies in Dasatinib versus untreated lung cancer were carried out [57,58]. One Dasatinib study was designed to elucidate signaling pathways and potential targets.…”