CHD1 Promotes Sensitivity to Aurora Kinase Inhibitors by Suppressing Interaction of AURKA with Its Coactivator TPX2

Authors

Haoyan Li
Yin Wang
Kevin Lin
Varadha Balaji Venkadakrishnan
Martin Bakht
Wei Shi
Chenling Meng
Jie Zhang
Kaitlyn Tremble
Xin Liang
Jian H Song
Xu Feng
Vivien Van
Pingna Deng
Jared K Burks
Ana Aparicio
Khandan Keyomarsi
Junjie Chen
Yue Lu
Himisha Beltran
Di Zhao

Publication Date

9-2-2022

Journal

Cancer Research

Abstract

UNLABELLED: Clinical studies have shown that subsets of patients with cancer achieve a significant benefit from Aurora kinase inhibitors, suggesting an urgent need to identify biomarkers for predicting drug response. Chromodomain helicase DNA binding protein 1 (CHD1) is involved in chromatin remodeling, DNA repair, and transcriptional plasticity. Prior studies have demonstrated that CHD1 has distinct expression patterns in cancers with different molecular features, but its impact on drug responsiveness remains understudied. Here, we show that CHD1 promotes the susceptibility of prostate cancer cells to inhibitors targeting Aurora kinases, while depletion of CHD1 impairs their efficacy in vitro and in vivo. Pan-cancer drug sensitivity analyses revealed that high expression of CHD1 was associated with increased sensitivity to Aurora kinase A (AURKA) inhibitors. Mechanistically, KPNA2 served as a direct target of CHD1 and suppressed the interaction of AURKA with the coactivator TPX2, thereby rendering cancer cells more vulnerable to AURKA inhibitors. Consistent with previous research reporting that loss of PTEN elevates CHD1 levels, studies in a genetically engineered mouse model, patient-derived organoids, and patient samples showed that PTEN defects are associated with a better response to AURKA inhibition in advanced prostate cancer. These observations demonstrate that CHD1 plays an important role in modulating Aurora kinases and drug sensitivities, providing new insights into biomarker-driven therapies targeting Aurora kinases for future clinical studies.

SIGNIFICANCE: CHD1 plays a critical role in controlling AURKA activation and promoting Aurora kinase inhibitor sensitivity, providing a potential clinical biomarker to guide cancer treatment.

Keywords

Animals, Antineoplastic Agents, Aurora Kinase A, Cell Cycle Proteins, Cell Line, Tumor, DNA Helicases, DNA-Binding Proteins, Humans, Male, Mice, Microtubule-Associated Proteins, Prostatic Neoplasms, Protein Kinase Inhibitors

DOI

10.1158/0008-5472.CAN-22-0631

PMID

35771632

PMCID

PMC9444962

PubMedCentral® Posted Date

3-2-2023

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes