Journal Article

Disruption of the anaphase-promoting complex confers resistance to TTK inhibitors in triple-negative breast cancer

Silvester, J., Elia, A. C., Haibe-Kains, B., Mer, A. S., Ba-alawi, W., Duncan, M. H., Mak, T. W., Thu, K. L., Smirnov, P., Cescon, D. W., Elliott, M. J., Safikhani, Z.

2018

Overview

TTK protein kinase (TTK), also known as Monopolar spindle 1 (MPS1), is a key regulator of the spindle assembly checkpoint (SAC), which functions to maintain genomic integrity. TTK has emerged as a promising therapeutic target in human cancers, including triple-negative breast cancer (TNBC). Several TTK inhibitors (TTKis) are being evaluated in clinical trials, and an understanding of the mechanisms mediating TTKi sensitivity and resistance could inform the successful development of this class of agents. We evaluated the cellular effects of the potent clinical TTKi CFI-402257 in TNBC models. CFI-402257 induced apoptosis and potentiated aneuploidy in TNBC lines by accelerating progression through mitosis and inducing mitotic segregation errors. We used genome-wide CRISPR/Cas9 screens in multiple TNBC cell lines to identify mechanisms of resistance to CFI-402257. Our functional genomic screens identified members of the anaphase-promoting complex/cyclosome (APC/C) complex, which promotes mitotic progression following inactivation of the SAC. Several screen candidates were validated to confer resistance to CFI-402257 and other TTKis using CRISPR/Cas9 and siRNA methods. These findings extend the observation that impairment of the APC/C enables cells to tolerate genomic instability caused by SAC inactivation, and support the notion that a measure of APC/C function could predict the response to TTK inhibition. Indeed, an APC/C gene expression signature is significantly associated with CFI-402257 response in breast and lung adenocarcinoma cell line panels. This expression signature, along with somatic alterations in genes involved in mitotic progression, represent potential biomarkers that could be evaluated in ongoing clinical trials of CFI-402257 or other TTKis.

• Publisher: National Academy of Sciences
• Subject: Adenocarcinoma / Adenomatous polyposis coli / Anaphase / Anaphase-promoting complex / Anaphase-Promoting Complex-Cyclosome - genetics / Anaphase-Promoting Complex-Cyclosome - metabolism / Aneuploidy / Apoptosis / Biological Sciences / Biomarkers / Breast cancer / C gene / Cancer / Cell Cycle Proteins - antagonists & inhibitors / Cell Cycle Proteins - metabolism / Cell division / Cell Line, Tumor / Clinical trials / CRISPR / Deactivation / Drug Resistance, Neoplasm / Female / Gene expression / Genomes / Genomic instability / Genomic Instability - drug effects / Genomics / Humans / Inactivation / Inhibitors / Kinases / Lungs / Medical research / Medical Sciences / Mitosis / Mitosis - drug effects / PNAS Plus / Protein kinase / Protein Kinase Inhibitors - pharmacology / Protein-Serine-Threonine Kinases - antagonists & inhibitors / Protein-Serine-Threonine Kinases - metabolism / Protein-Tyrosine Kinases - antagonists & inhibitors / Protein-Tyrosine Kinases - metabolism / Pyrazoles - pharmacology / Pyrimidines - pharmacology / Screens / siRNA / Stability / Therapeutic applications / Triple Negative Breast Neoplasms - drug therapy / Triple Negative Breast Neoplasms - enzymology / Triple Negative Breast Neoplasms - genetics / Triple Negative Breast Neoplasms - physiopathology