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ORIGINAL RESEARCH article
Front. Oncol.
Sec. Cancer Molecular Targets and Therapeutics
Volume 14 - 2024 |
doi: 10.3389/fonc.2024.1447807
Dual TTK/PLK1 inhibition has potent anticancer activity in TNBC as monotherapy and in combination
Provisionally accepted- 1 Basilea Pharmaceutica (Switzerland), Basel, Switzerland
- 2 Oncolines B.V., Oss, Netherlands
- 3 Other, Oss, Netherlands
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.
Keywords: BAL0891, mitotic checkpoint inhibitor, plk1, SAC, Ttk, MPS-1
Received: 12 Jun 2024; Accepted: 23 Jul 2024.
Copyright: © 2024 Zanini, Forster-Gross, Bachmann, Brüngger, McSheehy, Litherland, Burger, Groner, Roceri, Bury, Stieger, Willemsen-Seegers, de Man, Vu-Pham, van Riel, Zaman, buijsman, Kellenberger and Lane. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Nicole Forster-Gross, Basilea Pharmaceutica (Switzerland), Basel, Switzerland
Felix Bachmann, Basilea Pharmaceutica (Switzerland), Basel, Switzerland
Paul McSheehy, Basilea Pharmaceutica (Switzerland), Basel, Switzerland
Karin Burger, Basilea Pharmaceutica (Switzerland), Basel, Switzerland
Anna C. Groner, Basilea Pharmaceutica (Switzerland), Basel, Switzerland
Mila Roceri, Basilea Pharmaceutica (Switzerland), Basel, Switzerland
Luc Bury, Basilea Pharmaceutica (Switzerland), Basel, Switzerland
Martin Stieger, Basilea Pharmaceutica (Switzerland), Basel, Switzerland
Nicole Willemsen-Seegers, Oncolines B.V., Oss, Netherlands
Jos de Man, Other, Oss, Netherlands
Diep Vu-Pham, Other, Oss, Netherlands
Helma W. van Riel, Oncolines B.V., Oss, Netherlands
Rogier C. buijsman, Other, Oss, Netherlands
Laurenz Kellenberger, Basilea Pharmaceutica (Switzerland), Basel, Switzerland
Heidi A. Lane, Basilea Pharmaceutica (Switzerland), Basel, Switzerland
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