Varmeh, S. | bioRxiv Science

bioRxiv2022

Polo-like kinase-1 Inhibitors and the Antiandrogen Abiraterone Synergistically Disrupt Mitosis and Kill Cancer Cells of Disparate Origin Independently of Androgen Receptor Signaling

Abiraterone, a standard treatment for metastatic castrate-resistant prostate cancer (mCRPC), slows disease progression by abrogating androgen synthesis and antagonizing the androgen receptor (AR). We report that inhibitors of the mitotic kinase Plk1, including the clinically active third-generation Plk1 inhibitor onvansertib, when co-administered with abiraterone, synergistically kill cancer cells from a wide variety of tumor types in an androgen-independent manner, both in vitro and in vivo. Abiraterone treatment alone results in defects in mitotic spindle orientation, failure of complete chromosome condensation, and upregulation of mitosis and mitotic-spindle related gene sets independently of its effects on AR signaling. These effects, while mild following abiraterone monotherapy, result in profound sensitization to the anti-mitotic effects of Plk1 inhibition, leading to spindle assembly checkpoint-dependent mitotic cell death and entosis. In a murine PDX model of mCRPC, combined onvansertib and abiraterone resulted in enhanced mitotic arrest and dramatic inhibition of tumor cell growth compared to either agent alone. STATEMENT OF SIGNIFICANCEA phase 2 clinical trial is underway (NCT03414034) testing combined Plk1 inhibitor onvansertib and abiraterone in mCRPC patients with nascent abiraterone resistance. Our work establishes a mechanistic basis for that trial and indicates that combined abiraterone and onvansertib co-treatment may have broad utility for cancer treatment beyond mCRPC.

cancer biology↗

bioRxiv2018

Transite: A computational motif-based analysis platform that identifies RNA-binding proteins modulating changes in gene expression

RNA-binding proteins (RBPs) play critical roles in regulating gene expression by modulating splicing, RNA stability, and protein translation. In response to various stimuli, alterations in RBP function contribute to global changes in gene expression, but identifying which specific RBPs are responsible for the observed changes in gene expression patterns remains an unmet need. Here, we present Transite a multi-pronged computational approach that systematically infers RBPs influencing gene expression changes through alterations in RNA stability and degradation. As a proof of principle, we applied Transite to public RNA expression data from human patients with non-small cell lung cancer whose tumors were sampled at diagnosis, or after recurrence following treatment with platinum-based chemotherapy. Transite implicated known RBP regulators of the DNA damage response and identified hnRNPC as a new modulator of chemotherapeutic resistance, which we subsequently validated experimentally. Transite serves as a generalizable framework for the identification of RBPs responsible for gene expression changes that drive cell-state transitions and adds additional value to the vast wealth of publicly-available gene expression data.

bioinformatics↗