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

Area of Science:

• Oncology
• Molecular Biology
• Genomics

Background:

• High-grade serous ovarian carcinoma (HGSOC) is a lethal gynecological cancer with limited targeted therapy options.
• HGSOC tumors display genomic instability and frequent protein kinome alterations, yet few kinases are therapeutically targeted.
• Understanding the kinome landscape is crucial for identifying novel therapeutic strategies.

Purpose of the Study:

• To map the kinome landscape of HGSOC tumors.
• To identify novel, therapeutically targetable kinases in HGSOC.
• To investigate the role of MRCKA (CDC42BPA) as a potential therapeutic target.

Main Methods:

• Multiplexed inhibitor beads and mass spectrometry were used to profile the kinome in HGSOC patient tumors and xenograft models.
• Loss-of-function analysis was performed to assess the role of newly identified kinases.
• Characterization of MRCKA knockdown effects and inhibition using BDP9066 in HGSOC cell lines.

Main Results:

• The kinome profiling revealed a signature including known HGSOC drivers and previously unexplored kinases.
• Loss-of-function analysis identified MRCKA (CDC42BPA) as a putative therapeutic target.
• MRCKA knockdown affected cell cycle, focal adhesion, actin remodeling, migration, proliferation, and survival.
• MRCKA inhibition with BDP9066 reduced proliferation, spheroid formation, and induced apoptosis in HGSOC cells.

Conclusions:

• MRCKA is integral to key signaling pathways driving HGSOC progression.
• MRCKA represents a promising therapeutic target for HGSOC treatment.
• Targeting MRCKA may offer a novel strategy for managing this aggressive gynecological cancer.