序贯抑制CDK4/6和有丝分裂激酶TTK作为三阴性乳腺癌细胞系的潜在治疗方法

Triple-negative breast cancer (TNBC) is a poor-prognostic subtype. TNBC cells have uncontrolled cell proliferation, genetic instability, and elevated rates of metastasis. Lacking targeted therapies, chemotherapy is the primary treatment option. Mitotic kinases that maintain genomic stability, such as Threonine Tyrosine Kinase (TTK), exhibit increased expression in TNBC patients. TTK regulates the spindle assembly checkpoint, and its overexpression contributes to centrosome amplification, chromosome instability, and early metastasis. Palbociclib, a CDK4/6 inhibitor known to induce cellular senescence in tumors, is approved against luminal BC but not TNBC. Due to the reduced sensitivity of non-cycling cells to chemotherapeutic drugs, simultaneous association between Palbociclib and different chemotherapeutic agents has shown antagonistic effects. Preliminary data shows no significant decrease in the viability of TNBC cell-lines after simultaneous inhibition of TTK and CDK4/6. Based on studies stating that a sequential treatment with Palbociclib followed by a chemotherapeutic agent (paclitaxel) decreases TNBC cell-line viability, and our preliminary data showing that TTK inhibition restores the expression of G1/S regulators such as Rb, our study aims to evaluate if resistant TNBC cells may be sensitive to sequential treatment of CDK4/6 inhibition followed by mitotic kinase TTK inhibition. Twenty-four hours after seeding MDA-MB-231 and MDA-MB-157 TNBC cell lines, Palbociclib (PD0332991) was added at increasing concentrations. Twenty-four hours later, TTK inhibitor (BAY1217389) was added at a constant IC 50 concentration. The MTT Assay was performed after 96 hours of incubation. Pre-treatment with Palbociclib followed by a constant IC 50 concentration of TTK inhibitor showed significant decrease in MDA-MB-157 cell line viability. Results state that a sequential treatment strategy with Palbociclib followed by TTK inhibitor treatment can be a potential therapeutic approach for certain populations with TNBC. Differences associated with drug responses can be attributed to the difference in levels of cell cycle regulators in TNBC cell lines, which will be investigated further on. Results allowed the reduction of drug levels and toxicity, while potentially improving safety and efficacy for clinical use.