Potential biomarkers associated with prognosis and trastuzumab response in HER2+ breast cancer

CASTRO GUIJARRO, AC; MONDACA, JM; VANDERHOEVEN, F; REDONDO, A; SANCHEZ, AM; FLAMINI, MI

Buenos Aires

Simposio; Simposio Internacional Frontiers in Bioscience 4; 2023

Breast cancer (BC) is the most common malignancy among women. Around 25% of BC overexpressed the human epidermal growth factor receptor2 (HER2), associated with a worse prognosis. Therefore, anti-HER2 drugs have been developed like trastuzumab (Tz), ado-trastuzumab-emtansine (T-DM1), and lapatinib (Lp). Although Tz is the standard treatment, some patients suffer resistance. Fully understanding the actions of anti-HER2 drugs and the search for biomarkers that make it possible to better predict the evolution of the disease and to select the optimal therapeutic options are imperative. In this study, we evaluated Tz/T-DM1/Lp, alone or in combination, to determine their role in tumor progression and to define potential biomarkers. We identified genes associated with cell motility differential expressed between Tz/T-DM1-resistant and sensitive cells. We showed that Tz/T-DM1/Lp decrease cell viability, mainly in combinations. We determined synergism between Tz/T-DM1 and Lp, being possible a dose reduction to achieve the same effects. We found that Tz/T-DM1+Lp reduce cell adhesion and migration. We demonstrated that anti-HER2 drugs induce FAK nuclear and cortactin peri-nuclear localization. We observed that combinations inhibit the expression of essential proteins for metastasis like SRC, FAK, and paxillin. We found that VCL mRNA levels have potential value to predict survival, meanwhile VCL and CTTN mRNA levels to discriminate between Tz-responders and Tz-non-responders in HER2+BC patients. We found that silencing FAK/paxillin/cortactin differently affect migration capacity in Tz-resistant vs. sensitive cells. We evidenced that Tz-resistant cells have vinculin and cortactin enhanced expression than sensitives. In conclusion, we demonstrate that combined treatments are promising. Low doses of Tz/T-DM1+Lp efficiently inhibit adhesion and migration by downregulating critical proteins and affecting their localization. We identify potentially prognostic and predictive biomarkers promising for personalized BC management that would allow efficient patient selection to mitigate Tz-resistance. Furthermore, we propose that vinculin and cortactin might contribute to Tz-sensibility/resistance in BC cells.