journal contribution
posted on 2023-03-30, 23:44 authored by Aleksandra Olow, Zhongzhong Chen, R. Hannes Niedner, Denise M. Wolf, Christina Yau, Aleksandr Pankov, Evelyn Pei Rong Lee, Lamorna Brown-Swigart, Laura J. van ‘t Veer, Jean-Philippe Coppé Description of additional methods and procedures used in the study. Also includes Supplementary References.
Funding
the Friends for an Earlier Breast Cancer Treatment, UCSF Breast Oncology Program Developmental Research Program, T1 Catalyst Award
NIH UCSF SPORE project 2, National Institute of General Medical Sciences
National Science Foundation, a gift from the “Atwaters,” and the Angela and Shu Kai Chan Endowed chair
History
ARTICLE ABSTRACT
Kinase inhibitors are used widely to treat various cancers, but adaptive reprogramming of kinase cascades and activation of feedback loop mechanisms often contribute to therapeutic resistance. Determining comprehensive, accurate maps of kinase circuits may therefore help elucidate mechanisms of response and resistance to kinase inhibitor therapies. In this study, we identified and validated phosphorylatable target sites across human cell and tissue types to generate PhosphoAtlas, a map of 1,733 functionally interconnected proteins comprising the human phospho-reactome. A systematic curation approach was used to distill protein phosphorylation data cross-referenced from 38 public resources. We demonstrated how a catalog of 2,617 stringently verified heptameric peptide regions at the catalytic interface of kinases and substrates could expose mutations that recurrently perturb specific phospho-hubs. In silico mapping of 2,896 nonsynonymous tumor variants identified from thousands of tumor tissues also revealed that normal and aberrant catalytic interactions co-occur frequently, showing how tumors systematically hijack, as well as spare, particular subnetworks. Overall, our work provides an important new resource for interrogating the human tumor kinome to strategically identify therapeutically actionable kinase networks that drive tumorigenesis. Cancer Res; 76(7); 1733–45. ©2016 AACR.
