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Phosphoprotein-based biomarkers as predictors for cancer therapy.

Authors :
Carter AM
Tan C
Pozo K
Telange R
Molinaro R
Guo A
De Rosa E
Martinez JO
Zhang S
Kumar N
Takahashi M
Wiederhold T
Ghayee HK
Oltmann SC
Pacak K
Woltering EA
Hatanpaa KJ
Nwariaku FE
Grubbs EG
Gill AJ
Robinson B
Gillardon F
Reddy S
Jaskula-Sztul R
Mobley JA
Mukhtar MS
Tasciotti E
Chen H
Bibb JA
Source :
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2020 Aug 04; Vol. 117 (31), pp. 18401-18411. Date of Electronic Publication: 2020 Jul 20.
Publication Year :
2020

Abstract

Disparities in cancer patient responses have prompted widespread searches to identify differences in sensitive vs. nonsensitive populations and form the basis of personalized medicine. This customized approach is dependent upon the development of pathway-specific therapeutics in conjunction with biomarkers that predict patient responses. Here, we show that Cdk5 drives growth in subgroups of patients with multiple types of neuroendocrine neoplasms. Phosphoproteomics and high throughput screening identified phosphorylation sites downstream of Cdk5. These phosphorylation events serve as biomarkers and effectively pinpoint Cdk5-driven tumors. Toward achieving targeted therapy, we demonstrate that mouse models of neuroendocrine cancer are responsive to selective Cdk5 inhibitors and biomimetic nanoparticles are effective vehicles for enhanced tumor targeting and reduction of drug toxicity. Finally, we show that biomarkers of Cdk5-dependent tumors effectively predict response to anti-Cdk5 therapy in patient-derived xenografts. Thus, a phosphoprotein-based diagnostic assay combined with Cdk5-targeted therapy is a rational treatment approach for neuroendocrine malignancies.<br />Competing Interests: The authors declare no competing interest.

Details

Language :
English
ISSN :
1091-6490
Volume :
117
Issue :
31
Database :
MEDLINE
Journal :
Proceedings of the National Academy of Sciences of the United States of America
Publication Type :
Academic Journal
Accession number :
32690709
Full Text :
https://doi.org/10.1073/pnas.2010103117