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Article: Pathway-based identification of biomarkers for targeted therapeutics: Personalized oncology with PI3K pathway inhibitors

TitlePathway-based identification of biomarkers for targeted therapeutics: Personalized oncology with PI3K pathway inhibitors
Authors
Issue Date2010
Citation
Science Translational Medicine, 2010, v. 2 n. 43 How to Cite?
AbstractAlthough we have made great progress in understanding the complex genetic alterations that underlie human cancer, it has proven difficult to identify which molecularly targeted therapeutics will benefit which patients. Drug-specific modulation of oncogenic signaling pathways in specific patient subpopulations can predict responsiveness to targeted therapy. Here, we report a pathway-based phosphoprofiling approach to identify and quantify clinically relevant, drug-specific biomarkers for phosphatidylinositol 3-kinase (PI3K) pathway inhibitors that target AKT, phosphoinositide-dependent kinase 1 (PDK1), and PI3K-mammalian target of rapamycin (mTOR). We quantified 375 nonredundant PI3K pathway-relevant phosphopeptides, all containing AKT, PDK1, ormitogen-activated protein kinase substrate recognition motifs. Of these phosphopeptides, 71 were drug-regulated, 11 of them by all three inhibitors. Drug-modulated phosphoproteins were enriched for involvement in cytoskeletal reorganization (filamin, stathmin, dynamin, PAK4, and PTPN14), vesicle transport (LARP1, VPS13D, and SLC20A1), and protein translation (S6RP and PRAS40).We then generated phosphospecific antibodies against selected, drug-regulated phosphorylation sites that would be suitable as biomarker tools for PI3K pathway inhibitors. As proof of concept, we show clinical translation feasibility for an antibody against phospho-PRAS40 Thr246. Evaluation of binding of this antibody in human cancer cell lines, a PTEN (phosphatase and tensin homolog deleted from chromosome 10)-deficient mouse prostate tumor model, and triple-negative breast tumor tissues showed that phospho-PRAS40 Thr246 positively correlates with PI3K pathway activation and predicts AKT inhibitor sensitivity. In contrast to phosphorylation of AKT Thr308, the phospho-PRAS40 Thr246 epitope is highly stable in tissue samples and thus is ideal for immunohistochemistry. In summary, our study illustrates a rational approach for discovery of drug-specific biomarkers toward development of patient-tailored treatments.
Persistent Identifierhttp://hdl.handle.net/10722/156002
ISSN
2015 Impact Factor: 16.264
2015 SCImago Journal Rankings: 8.931
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorAndersen, JNen_US
dc.contributor.authorSathyanarayanan, Sen_US
dc.contributor.authorDi Bacco, Aen_US
dc.contributor.authorChi, Aen_US
dc.contributor.authorZhang, Ten_US
dc.contributor.authorChen, AHen_US
dc.contributor.authorDolinski, Ben_US
dc.contributor.authorKraus, Men_US
dc.contributor.authorRoberts, Ben_US
dc.contributor.authorArthur, Wen_US
dc.contributor.authorKlinghoffer, RAen_US
dc.contributor.authorGargano, Den_US
dc.contributor.authorLi, Xen_US
dc.contributor.authorFeldman, Ien_US
dc.contributor.authorLynch, Ben_US
dc.contributor.authorRush, Jen_US
dc.contributor.authorHendrickson, RCen_US
dc.contributor.authorBlumeJensen, Pen_US
dc.contributor.authorPaweletz, CPen_US
dc.date.accessioned2012-08-08T08:39:25Z-
dc.date.available2012-08-08T08:39:25Z-
dc.date.issued2010en_US
dc.identifier.citationScience Translational Medicine, 2010, v. 2 n. 43en_US
dc.identifier.issn1946-6234en_US
dc.identifier.urihttp://hdl.handle.net/10722/156002-
dc.description.abstractAlthough we have made great progress in understanding the complex genetic alterations that underlie human cancer, it has proven difficult to identify which molecularly targeted therapeutics will benefit which patients. Drug-specific modulation of oncogenic signaling pathways in specific patient subpopulations can predict responsiveness to targeted therapy. Here, we report a pathway-based phosphoprofiling approach to identify and quantify clinically relevant, drug-specific biomarkers for phosphatidylinositol 3-kinase (PI3K) pathway inhibitors that target AKT, phosphoinositide-dependent kinase 1 (PDK1), and PI3K-mammalian target of rapamycin (mTOR). We quantified 375 nonredundant PI3K pathway-relevant phosphopeptides, all containing AKT, PDK1, ormitogen-activated protein kinase substrate recognition motifs. Of these phosphopeptides, 71 were drug-regulated, 11 of them by all three inhibitors. Drug-modulated phosphoproteins were enriched for involvement in cytoskeletal reorganization (filamin, stathmin, dynamin, PAK4, and PTPN14), vesicle transport (LARP1, VPS13D, and SLC20A1), and protein translation (S6RP and PRAS40).We then generated phosphospecific antibodies against selected, drug-regulated phosphorylation sites that would be suitable as biomarker tools for PI3K pathway inhibitors. As proof of concept, we show clinical translation feasibility for an antibody against phospho-PRAS40 Thr246. Evaluation of binding of this antibody in human cancer cell lines, a PTEN (phosphatase and tensin homolog deleted from chromosome 10)-deficient mouse prostate tumor model, and triple-negative breast tumor tissues showed that phospho-PRAS40 Thr246 positively correlates with PI3K pathway activation and predicts AKT inhibitor sensitivity. In contrast to phosphorylation of AKT Thr308, the phospho-PRAS40 Thr246 epitope is highly stable in tissue samples and thus is ideal for immunohistochemistry. In summary, our study illustrates a rational approach for discovery of drug-specific biomarkers toward development of patient-tailored treatments.en_US
dc.languageengen_US
dc.relation.ispartofScience Translational Medicineen_US
dc.titlePathway-based identification of biomarkers for targeted therapeutics: Personalized oncology with PI3K pathway inhibitorsen_US
dc.typeArticleen_US
dc.identifier.emailChen, AH:hrllchy@hkucc.hku.hken_US
dc.identifier.authorityChen, AH=rp01240en_US
dc.identifier.doi10.1126/scitranslmed.3001065en_US
dc.identifier.pmid20686178-
dc.identifier.scopuseid_2-s2.0-77955648969en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-77955648969&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume2en_US
dc.identifier.issue43en_US
dc.identifier.isiWOS:000288434200003-
dc.identifier.f10005188956-
dc.identifier.scopusauthoridAndersen, JN=35512446300en_US
dc.identifier.scopusauthoridSathyanarayanan, S=6506689732en_US
dc.identifier.scopusauthoridDi Bacco, A=6603272929en_US
dc.identifier.scopusauthoridChi, A=8695748800en_US
dc.identifier.scopusauthoridZhang, T=8087066400en_US
dc.identifier.scopusauthoridChen, AH=7403392103en_US
dc.identifier.scopusauthoridDolinski, B=7801344570en_US
dc.identifier.scopusauthoridKraus, M=7202455637en_US
dc.identifier.scopusauthoridRoberts, B=8896592100en_US
dc.identifier.scopusauthoridArthur, W=7005300506en_US
dc.identifier.scopusauthoridKlinghoffer, RA=6602776396en_US
dc.identifier.scopusauthoridGargano, D=35185144900en_US
dc.identifier.scopusauthoridLi, X=35237863400en_US
dc.identifier.scopusauthoridFeldman, I=24066357400en_US
dc.identifier.scopusauthoridLynch, B=36236899400en_US
dc.identifier.scopusauthoridRush, J=34573475000en_US
dc.identifier.scopusauthoridHendrickson, RC=7005198204en_US
dc.identifier.scopusauthoridBlumeJensen, P=6602824234en_US
dc.identifier.scopusauthoridPaweletz, CP=6701654303en_US
dc.identifier.citeulike7585661-

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