Functional proteomics interrogation of the kinome identifies MRCKA as a therapeutic target in high-grade serous ovarian carcinoma

Alison M. Kurimchak; Carlos Herrera-Montávez; Jennifer Brown; Katherine J. Johnson; Valerie L. Sodi; Nishi Srivastava; Vikas Kumar; Safoora Deihimi; Shane  O'Brien; Suraj Peri; Gina M. Mantia-Smaldone; Angela Jain; Ryan M. Winters; Kathy Q. Cai; Jonathan Chernoff; Denise C. Connolly; James S. Duncan

doi:10.1126/scisignal.aax8238

Functional proteomics interrogation of the kinome identifies MRCKA as a therapeutic target in high-grade serous ovarian carcinoma

Alison M. Kurimchak, Carlos Herrera-Montávez, Jennifer Brown, Katherine J. Johnson, Valerie L. Sodi, Nishi Srivastava, Vikas Kumar, Safoora Deihimi, Shane O'Brien, Suraj Peri, Gina M. Mantia-Smaldone, Angela Jain, Ryan M. Winters, Kathy Q. Cai, Jonathan Chernoff, Denise C. Connolly, James S. Duncan

Research output: Contribution to journal › Article › peer-review

22 Scopus citations

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.

Original language	English
Article number	eaax8238
Journal	Science Signaling
Volume	13
Issue number	619
DOIs	https://doi.org/10.1126/scisignal.aax8238
State	Published - Feb 18 2020

Keywords

Biomarkers, Tumor/antagonists & inhibitors
Cell Line, Tumor
Cell Movement/genetics
Cell Proliferation/genetics
Cystadenocarcinoma, Serous/drug therapy
Female
Gene Expression Regulation, Neoplastic
Humans
Mass Spectrometry/methods
Molecular Targeted Therapy/methods
Myotonin-Protein Kinase/antagonists & inhibitors
Neoplasm Grading
Ovarian Neoplasms/drug therapy
Protein Kinases/genetics
Proteomics/methods
RNA Interference
Signal Transduction/drug effects

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10.1126/scisignal.aax8238

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Kurimchak, A. M., Herrera-Montávez, C., Brown, J., Johnson, K. J., Sodi, V. L., Srivastava, N., Kumar, V., Deihimi, S., O'Brien, S., Peri, S., Mantia-Smaldone, G. M., Jain, A., Winters, R. M., Cai, K. Q., Chernoff, J., Connolly, D. C., & Duncan, J. S. (2020). Functional proteomics interrogation of the kinome identifies MRCKA as a therapeutic target in high-grade serous ovarian carcinoma. Science Signaling, 13(619), Article eaax8238. https://doi.org/10.1126/scisignal.aax8238

@article{3de491ce1787462793d3aeeb7ca74d3c,

title = "Functional proteomics interrogation of the kinome identifies MRCKA as a therapeutic target in high-grade serous ovarian carcinoma",

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.",

keywords = "Biomarkers, Tumor/antagonists & inhibitors, Cell Line, Tumor, Cell Movement/genetics, Cell Proliferation/genetics, Cystadenocarcinoma, Serous/drug therapy, Female, Gene Expression Regulation, Neoplastic, Humans, Mass Spectrometry/methods, Molecular Targeted Therapy/methods, Myotonin-Protein Kinase/antagonists & inhibitors, Neoplasm Grading, Ovarian Neoplasms/drug therapy, Protein Kinases/genetics, Proteomics/methods, RNA Interference, Signal Transduction/drug effects",

author = "Kurimchak, {Alison M.} and Carlos Herrera-Mont{\'a}vez and Jennifer Brown and Johnson, {Katherine J.} and Sodi, {Valerie L.} and Nishi Srivastava and Vikas Kumar and Safoora Deihimi and Shane O'Brien and Suraj Peri and Mantia-Smaldone, {Gina M.} and Angela Jain and Winters, {Ryan M.} and Cai, {Kathy Q.} and Jonathan Chernoff and Connolly, {Denise C.} and Duncan, {James S.}",

note = "Copyright {\textcopyright} 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.",

year = "2020",

month = feb,

day = "18",

doi = "10.1126/scisignal.aax8238",

language = "English",

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journal = "Science Signaling",

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Kurimchak, AM, Herrera-Montávez, C, Brown, J, Johnson, KJ, Sodi, VL, Srivastava, N, Kumar, V, Deihimi, S, O'Brien, S, Peri, S, Mantia-Smaldone, GM , Jain, A, Winters, RM, Cai, KQ , Chernoff, J , Connolly, DC & Duncan, JS 2020, 'Functional proteomics interrogation of the kinome identifies MRCKA as a therapeutic target in high-grade serous ovarian carcinoma', Science Signaling, vol. 13, no. 619, eaax8238. https://doi.org/10.1126/scisignal.aax8238

TY - JOUR

T1 - Functional proteomics interrogation of the kinome identifies MRCKA as a therapeutic target in high-grade serous ovarian carcinoma

AU - Kurimchak, Alison M.

AU - Herrera-Montávez, Carlos

AU - Brown, Jennifer

AU - Johnson, Katherine J.

AU - Sodi, Valerie L.

AU - Srivastava, Nishi

AU - Kumar, Vikas

AU - Deihimi, Safoora

AU - O'Brien, Shane

AU - Peri, Suraj

AU - Mantia-Smaldone, Gina M.

AU - Jain, Angela

AU - Winters, Ryan M.

AU - Cai, Kathy Q.

AU - Chernoff, Jonathan

AU - Connolly, Denise C.

AU - Duncan, James S.

PY - 2020/2/18

Y1 - 2020/2/18

N2 - 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.

AB - 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.

KW - Biomarkers, Tumor/antagonists & inhibitors

KW - Cell Line, Tumor

KW - Cell Movement/genetics

KW - Cell Proliferation/genetics

KW - Cystadenocarcinoma, Serous/drug therapy

KW - Female

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Mass Spectrometry/methods

KW - Molecular Targeted Therapy/methods

KW - Myotonin-Protein Kinase/antagonists & inhibitors

KW - Neoplasm Grading

KW - Ovarian Neoplasms/drug therapy

KW - Protein Kinases/genetics

KW - Proteomics/methods

KW - RNA Interference

KW - Signal Transduction/drug effects

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UR - https://pubmed.ncbi.nlm.nih.gov/32071169/

U2 - 10.1126/scisignal.aax8238

DO - 10.1126/scisignal.aax8238

M3 - Article

C2 - 32071169

SN - 1945-0877

VL - 13

JO - Science Signaling

JF - Science Signaling

IS - 619

M1 - eaax8238

ER -

Functional proteomics interrogation of the kinome identifies MRCKA as a therapeutic target in high-grade serous ovarian carcinoma

Abstract

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Functional proteomics interrogation of the kinome identifies MRCKA as a therapeutic target in high-grade serous ovarian carcinoma

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