Polo-like Kinase 1 Inhibitors Demonstrate In Vitro and In Vivo Efficacy in Preclinical Models of Small Cell Lung Cancer

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2025 Feb 13

PMID 39941812

Authors

Guojing Zhang

Abbe Pannucci

Andrey A Ivanov

Jeffrey Switchenko

Shi-Yong Sun

Gabriel L Sica

Zhentao Liu

Yufei Huang

John C Schmitz

Taofeek K Owonikoko

Affiliations

Soon will be listed here.

Abstract

To investigate the preclinical efficacy and identify predictive biomarkers of polo-like kinase 1 (PLK1) inhibitors in small cell lung cancer (SCLC) models. We tested the cytotoxicity of selective PLK1 inhibitors (rigosertib, volasertib, and onvansertib) in a panel of SCLC cell lines. We confirmed the therapeutic efficacy of subcutaneous xenografts of representative cell lines and in four patient-derived xenograft models generated from patients with platinum-sensitive and platinum-resistant SCLC. We employed an integrated analysis of genomic and transcriptomic sequencing data to identify potential biomarkers of the activity and mechanisms of resistance in laboratory-derived resistance models. Volasertib, rigosertib, and onvansertib showed strong in vitro cytotoxicity at nanomolar concentrations in human SCLC cell lines. Rigosertib, volasertib, and onvansertib showed equivalent efficacy to that of standard care agents (irinotecan and cisplatin) in vivo with significant growth inhibition superior to cisplatin in PDX models of platinum-sensitive and platinum-resistant SCLC. There was an association between expression and disruptive or inactivation gene mutations, with greater efficacy of PLK1 inhibitors. Comparison of lab-derived onvansertib-resistant H526 cells to parental cells revealed differential gene expression with upregulation of , , , and and downregulation of , , , and highlighting the potential mechanisms of resistance in the clinical setting. We established the efficacy of PLK1 inhibitors in vitro and in vivo using PDX models of platinum-sensitive and resistant relapsed SCLC. An ongoing phase II trial is currently testing the efficacy of onvansertib in patients with SCLC (NCT05450965).

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