AUTHOR=Zanini Elisa , Forster-Gross Nicole , Bachmann Felix , Brüngger Adrian , McSheehy Paul , Litherland Karine , Burger Karin , Groner Anna C. , Roceri Mila , Bury Luc , Stieger Martin , Willemsen-Seegers Nicole , de Man Jos , Vu-Pham Diep , van Riel Helma W. E. , Zaman Guido J. R. , Buijsman Rogier C. , Kellenberger Laurenz , Lane Heidi A. 

TITLE=Dual TTK/PLK1 inhibition has potent anticancer activity in TNBC as monotherapy and in combination

JOURNAL=Frontiers in Oncology

VOLUME=Volume 14 - 2024

YEAR=2024

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2024.1447807

DOI=10.3389/fonc.2024.1447807

ISSN=2234-943X

ABSTRACT=Threonine Tyrosine Kinase (TTK) and Polo-Like Kinase 1 (PLK1) are common essential kinases that collaborate in activating the spindle assembly checkpoint (SAC) at the kinetochore ensuring appropriate chromosome alignment/segregation prior to mitotic exit. BAL0891 is a first in class, dual TTK/PLK1 inhibitor with a prolonged effect on TTK and a transient activity on PLK1. This unique profile potentiates SAC disruption, forcing tumor cells to aberrantly exit mitosis, with faster kinetics than observed with a TTK-specific inhibitor. With broad anti-proliferative activity across solid tumor cell lines in vitro, intermittent intravenous single-agent treatment of the MDA-MB-231 mouse model of human triple negative breast cancer (TNBC) induces profound tumor regressions associated with prolonged TTK and transient PLK1 in-tumor target occupancy. Furthermore, differential tumor responses across a panel of thirteen TNBC patient-derived xenograft models indicated profound anticancer activity in a sub-set. Using a flexible dosing approach, pathologically confirmed cures were observed in combination with paclitaxel, whereas synergy with carboplatin was schedule dependent. Hence, dual TTK/PLK1 inhibition represents a novel approach for the treatment of human cancer, including TNBC patients.