Akademik Veri Yönetim Sistemi
7th International Current Issues Congress on Medicine, Nursing, Midwifery, and Health Sciences, Sakarya, Türkiye, 27 - 29 Haziran 2025, cilt.1, ss.114-125, (Tam Metin Bildiri)
Introduction: Triple-negative breast
cancer (TNBC) is a highly aggressive and heterogeneous subtype characterized by
the absence of hormone receptors (ER, PR), and HER2 expression. Due to the lack
of these targets, TNBC does not respond to currently available targeted
therapies. The limited efficacy of standard treatment protocols underscores the
urgent need for novel therapeutic strategies. In this study, the individual and
combined anticancer effects of CA3, a YAP1 inhibitor targeting the Hippo
signaling pathway, and Docetaxel (DOC), a taxane-derived chemotherapeutic
agent, were investigated in the TNBC model cell line MDA-MB231.
Methods: The effects of CA3 and DOC on cell viability were determined using the MTT assay. Based on EC₅₀ values, combination treatments were applied at different concentrations. The resulting data were analyzed using the Loewe additivity model via Combenefit software to identify synergistic or antagonistic interactions.
Results: Analysis of the inhibition curve of CA3 on MDA-MB231 cells using the Hill model yielded an EC₅₀ value of 2.2 μM. Similarly, the EC₅₀ value for DOC was calculated as 17 nM. In combination experiments, a significant synergistic effect was observed when CA3 at 0.25 μM and 1 μM was combined with the dose of DOC allowing approximately 80% cell viability. Other combinations showed additive (non-interactive) effects, with no significant synergism or antagonism detected.
Discussion: Chemotherapy remains the mainstay of TNBC treatment; however, treatment responses are often limited, and resistance is frequently observed. In this context, targeting the Hippo/YAP1 signaling pathway, which regulates cell proliferation, apoptosis, and gene expression, emerges as a promising strategy. CA3 has been reported in the literature to exert anticancer effects in various cancer cell lines via YAP1 inhibition. In this study, CA3 also demonstrated significant inhibition as a single agent in MDA-MB231 cells.
Docetaxel, a member of the taxane class, induces apoptosis by disrupting microtubule dynamics and arresting mitosis. Its effectiveness at low nanomolar concentrations highlights its therapeutic value even in aggressive cancers such as TNBC. However, in clinical practice, acquired resistance to docetaxel, especially among younger patients, remains a significant challenge, thereby increasing interest in combination therapies.
The observation of synergistic effects at specific dose pairs in combination experiments suggests that the two agents may exert complementary effects via different molecular targets. While CA3 inhibits transcriptional control via YAP1, DOC induces mitotic blockade, potentially activating multiple apoptotic pathways simultaneously. This could explain the synergistic interactions observed particularly at sublethal concentrations.
However, the findings also indicate that synergy is dose-dependent. At higher concentrations of CA3 (e.g., 4 μM) or DOC, the combination did not provide additional benefits, possibly due to dose-related cytotoxicity or adaptive cellular responses to stress levels beyond a certain threshold. Therefore, determining optimal dosing ranges is critical to realizing the clinical potential of combination therapies.
Conclusion: This study demonstrated that the combination of the YAP1 inhibitor CA3 and DOC produced synergistic anticancer effects in the MDA-MB231 cell line at specific concentrations. The complementary mechanisms of action of these agents suggest that this combination could represent a novel approach to enhance chemotherapeutic efficacy in TNBC. Previous findings support the potential of CA3 to reduce chemoresistance and improve treatment response. Nonetheless, the promising in vitro results obtained here require further validation through in vivo models and clinical studies.
(This work was supported by Çanakkale Onsekiz Mart University The Scientific Research Coordination Unit, Project number: FLÖAP-2024-4844)