TY - JOUR
T1 - Pan-cancer proteogenomic investigations identify post-transcriptional kinase targets
AU - Elmas, Abdulkadir
AU - Tharakan, Serena
AU - Jaladanki, Suraj
AU - Galsky, Matthew D.
AU - Liu, Tao
AU - Huang, Kuan lin
N1 - Funding Information:
We acknowledge the participating patients and family who generously contributed to the data sets. We also acknowledge members of the CPTAC for helpful discussions. We thank the Center for Comparative Medicine and Surgery at Mount Sinai. This work was supported by the following grants: NCI CPTAC grant (U24CA210955), NIGMS R35GM138113, and ISMMS seed fund. The Tisch Cancer Institute and related research facilities are supported by P30 CA196521.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - Identifying genomic alterations of cancer proteins has guided the development of targeted therapies, but proteomic analyses are required to validate and reveal new treatment opportunities. Herein, we develop a new algorithm, OPPTI, to discover overexpressed kinase proteins across 10 cancer types using global mass spectrometry proteomics data of 1,071 cases. OPPTI outperforms existing methods by leveraging multiple co-expressed markers to identify targets overexpressed in a subset of tumors. OPPTI-identified overexpression of ERBB2 and EGFR proteins correlates with genomic amplifications, while CDK4/6, PDK1, and MET protein overexpression frequently occur without corresponding DNA- and RNA-level alterations. Analyzing CRISPR screen data, we confirm expression-driven dependencies of multiple currently-druggable and new target kinases whose expressions are validated by immunochemistry. Identified kinases are further associated with up-regulated phosphorylation levels of corresponding signaling pathways. Collectively, our results reveal protein-level aberrations—sometimes not observed by genomics—represent cancer vulnerabilities that may be targeted in precision oncology.
AB - Identifying genomic alterations of cancer proteins has guided the development of targeted therapies, but proteomic analyses are required to validate and reveal new treatment opportunities. Herein, we develop a new algorithm, OPPTI, to discover overexpressed kinase proteins across 10 cancer types using global mass spectrometry proteomics data of 1,071 cases. OPPTI outperforms existing methods by leveraging multiple co-expressed markers to identify targets overexpressed in a subset of tumors. OPPTI-identified overexpression of ERBB2 and EGFR proteins correlates with genomic amplifications, while CDK4/6, PDK1, and MET protein overexpression frequently occur without corresponding DNA- and RNA-level alterations. Analyzing CRISPR screen data, we confirm expression-driven dependencies of multiple currently-druggable and new target kinases whose expressions are validated by immunochemistry. Identified kinases are further associated with up-regulated phosphorylation levels of corresponding signaling pathways. Collectively, our results reveal protein-level aberrations—sometimes not observed by genomics—represent cancer vulnerabilities that may be targeted in precision oncology.
UR - http://www.scopus.com/inward/record.url?scp=85115353721&partnerID=8YFLogxK
U2 - 10.1038/s42003-021-02636-7
DO - 10.1038/s42003-021-02636-7
M3 - Article
C2 - 34552204
AN - SCOPUS:85115353721
SN - 2399-3642
VL - 4
JO - Communications Biology
JF - Communications Biology
IS - 1
M1 - 1112
ER -