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Functional proteomics interrogation of the kinome identifies MRCKA as a therapeutic target in high-grade serous ovarian carcinoma
Sci Signal. 2020 Feb 18;13(619)
PMID: 32071169    PMCID: PMC7294993    URL: https://www.ncbi.nlm.nih.gov/pubmed/32071169
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Abstract
High-grade serous ovarian carcinoma (HGSOC) is the most lethal gynecological cancer with few effective, targeted therapies. HGSOC tumors exhibit genomic instability with frequent alterations in the protein kinome; however, only a small fraction of the kinome has been therapeutically targeted in HGSOC. Using multiplexed inhibitor beads and mass spectrometry, we mapped the kinome landscape of HGSOC tumors from patients and patient-derived xenograft models. The data revealed a prevalent signature consisting of established HGSOC driver kinases, as well as several kinases previously unexplored in HGSOC. Loss-of-function analysis of these kinases in HGSOC cells indicated MRCKA (also known as CDC42BPA) as a putative therapeutic target. Characterization of the effects of MRCKA knockdown in established HGSOC cell lines demonstrated that MRCKA was integral to signaling that regulated the cell cycle checkpoint, focal adhesion, and actin remodeling, as well as cell migration, proliferation, and survival. Moreover, inhibition of MRCKA using the small-molecule BDP9066 decreased cell proliferation and spheroid formation and induced apoptosis in HGSOC cells, suggesting that MRCKA may be a promising therapeutic target for the treatment of HGSOC.
Notes
1937-9145 Kurimchak, Alison M ORCID: http://orcid.org/0000-0003-2608-0128 Herrera-Montavez, Carlos Brown, Jennifer ORCID: http://orcid.org/0000-0002-0545-1084 Johnson, Katherine J Sodi, Valerie Srivastava, Nishi Kumar, Vikas ORCID: http://orcid.org/0000-0001-7513-6832 Deihimi, Safoora O'Brien, Shane ORCID: http://orcid.org/0000-0002-8747-7834 Peri, Suraj Mantia-Smaldone, Gina M Jain, Angela Winters, Ryan M Cai, Kathy Q Chernoff, Jonathan ORCID: http://orcid.org/0000-0002-4803-7836 Connolly, Denise C Duncan, James S ORCID: http://orcid.org/0000-0002-1276-2745 Journal Article United States Sci Signal. 2020 Feb 18;13(619). pii: 13/619/eaax8238. doi: 10.1126/scisignal.aax8238.