Dual TTK/PLK1 inhibition has potent anticancer activity in TNBC as monotherapy and in combination
Elisa Zanini1, Nicole Forster-Gross1, Felix Bachmann1
1Basilea Pharmaceutica International Ltd, Allschwil, Switzerland.
Background:
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 and segregation prior to mitotic exit. Targeting of either TTK or PLK1 has been clinically evaluated in cancer patients; however, dual inhibitors have not yet been pursued. Here we present the in vitro and in vivo characterization of a first in class, dual TTK/PLK1 inhibitor (BAL0891).
Methods:
Mechanism of action studies utilized biochemical kinase and proteomics-based target-engagement assays. Cellular end-point assays included immunoblot- and flow cytometry-based cell cycle analyses and SAC integrity evaluation using immunoprecipitation and immunofluorescence approaches. Anticancer activity was assessed in vitro using cell growth assays and efficacy was evaluated, alone and in combination with paclitaxel and carboplatin, using mouse models of triple negative breast cancer (TNBC).
Results:
BAL0891 elicits a prolonged effect on TTK, with 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. Broad anti-proliferative activity was demonstrated across solid tumor cell lines in vitro. Moreover, intermittent intravenous single-agent BAL0891 treatment of the MDA-MB-231 mouse model of TNBC induced 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 subset (~40%). Using a flexible dosing approach, pathologically confirmed cures were observed in combination with paclitaxel, whereas synergy with carboplatin was schedule dependent.
Conclusions:
Dual TTK/PLK1 inhibition represents a novel approach for the treatment of human cancer, including TNBC patients, with a potential for potent anticancer activity and a favorable therapeutic index. Moreover, combination approaches may provide an avenue to expand responsive patient populations.
Insights
A novel dual inhibitor of Threonine tyrosine kinase (TTK) and polo-like kinase 1 (PLK1), BAL0891, shows potent anticancer activity in preclinical models, including triple-negative breast cancer (TNBC). This dual inhibition strategy offers a promising new avenue for cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Threonine tyrosine kinase (TTK) and polo-like kinase 1 (PLK1) are essential kinases involved in the spindle assembly checkpoint (SAC).
- Targeting TTK or PLK1 individually has shown clinical potential in cancer treatment.
- Dual inhibition of TTK and PLK1 has not been previously explored.
Purpose of the Study:
- To characterize the first-in-class dual TTK/PLK1 inhibitor, BAL0891.
- To evaluate the in vitro and in vivo anticancer activity of BAL0891.
- To assess the potential of dual TTK/PLK1 inhibition as a novel cancer therapeutic strategy.
Main Methods:
- Mechanism of action studies using biochemical and proteomics assays.
- Cellular assays including cell cycle analysis and SAC integrity evaluation.
- In vitro anti-proliferative assays and in vivo efficacy studies in triple-negative breast cancer (TNBC) mouse models, alone and in combination with chemotherapy.
Main Results:
- BAL0891 exhibits prolonged TTK inhibition and transient PLK1 inhibition, leading to accelerated SAC disruption and mitotic exit.
- Broad anti-proliferative activity was observed across various solid tumor cell lines.
- BAL0891 demonstrated significant tumor regressions in TNBC models and showed potent anticancer activity in approximately 40% of TNBC patient-derived xenografts.
- Combination therapy with paclitaxel resulted in cures, while synergy with carboplatin was schedule-dependent.
Conclusions:
- Dual TTK/PLK1 inhibition is a novel and promising approach for cancer treatment, particularly for TNBC.
- BAL0891 exhibits potent anticancer activity and a potentially favorable therapeutic index.
- Combination strategies may broaden the patient population responsive to this novel therapeutic approach.
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