PhD Scientific Days 2022

Budapest, 6-7 July 2022

Pathology and Oncology I. (Poster discussion will take place in the Aula during the Coffee Break)

Antitumor effects of farnesyl-transferase inhibitors on human lung adenocarcinoma model

Marcell Baranyi1 Zsófia Gábriel1,2, Balázs Hegedűs1,3, Tímár József1
Affiliations:
1: Semmelweis University, Department of Pathology, Forensic and Insurance Medicine, Budapest
2: Pázmány Péter Catholic University, Faculty of Information Technology, Budapest
3: University Medicine Essen–Ruhrlandklinik, Department of Thoracic Surgery Essen, Germany

Text of the abstract

Introduction
Introduction of farnesyl-transferase inhibitors (FTis) was anticipated as potential KRAS targeting therapy. Inhibition of farnesylation results in mislocalisation of farnesylated proteins like KRAS. Though the original aim was not achieved due to alternative geranylgeranylation of KRAS oncoprotein, FTis still possess wide-range antitumor potency. Thus, a number of clinical trials were initiated on solid and hematological tumor types. As inhibition of farnesylation affects multiple protein, mechanism of action of FTis is still to be explored.
Aims
Aim of this study is to explore mechanism of action of farnesyl-transferase inhibitors with special emphasis on changes of laminar network and small G proteins.
Methods
Investigation of effects of tipifarnib, a farnesyl-transferase inhibitor was performed on SW1573 lung adenocarcinoma cell line. Anti-proliferative and pro-apoptotic effects of tipifarnib was examined by time-lapse videomicroscopy and western blot analysis. Changes in laminar network and small G proteins was also investigated by western blot.
Results
Tipifarnib was able to block growth of SW1573 at a nanomolar concentration range. Time-lapse videomicroscopy and western blot analysis revealed that the inhibitor exerted proapoptotic and more profoundly, antiproliferative effects. Investigation of time-lapse videos revealed that tipifarnib treatment induced delayed cytokinesis in a large portion of proliferating cells. Further investigation showed that major changes occurred in the morphology of the nucleus and the laminar network. Western blot analysis revealed that accumulation of unfarnesylated lamins and small G protein RHEB and HRAS may also contributed to the defective proliferative ability of the treated cells.
Conclusion
Tipifarnib possesses efficient anti-tumor activity that is mainly mediated by inhibition of proliferation. Underlying mechanism involves defects of the laminar network as well as miclocalisation of certain small G proteins.

Funding: Present work was supported by ÚNKP-21-4-I-SE-24 New National Excellence Program of the Ministry for Innovation and Technology from the source of the National Research, Development and Innovation fund.