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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
Elisa Zanini Elisa Zanini 1Nicole Forster-Gross Nicole Forster-Gross 1*Felix Bachmann Felix Bachmann 1*Adrian Brüngger Adrian Brüngger 1Paul McSheehy Paul McSheehy 1*Karine Litherland Karine Litherland 1Karin Burger Karin Burger 1*Anna C. Groner Anna C. Groner 1*Mila Roceri Mila Roceri 1*Luc Bury Luc Bury 1*Martin Stieger Martin Stieger 1*Nicole Willemsen-Seegers Nicole Willemsen-Seegers 2*Jos de Man Jos de Man 3*Diep Vu-Pham Diep Vu-Pham 3*Helma W. van Riel Helma W. van Riel 2*Guido Zaman Guido Zaman 2Rogier C. buijsman Rogier C. buijsman 3*Laurenz Kellenberger Laurenz Kellenberger 1*Heidi A. Lane Heidi A. Lane 1*
  • 1 Basilea Pharmaceutica (Switzerland), Basel, Switzerland
  • 2 Oncolines B.V., Oss, Netherlands
  • 3 Other, Oss, Netherlands

The final, formatted version of the article will be published soon.

    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

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.