PhD Scientific Days 2020

Pathology and Oncology I. Posters

Horizontal Inhibition of the RAS/RAF and RAS/PI3K Pathways in BRAF Mutant Cancer Cell Lines

Előadó neve

Rittler, Dominika

Előadó munkahelye

2nd Department of Pathology

Előadó telefonszáma

+36306762803

Előadó e-mail címe

rittlerdomi@gmail.com

Az előadás címe

Horizontal Inhibition of the RAS/RAF and RAS/PI3K Pathways in BRAF Mutant Cancer Cell Lines

Szerző(k) neve és munkahelye

Dominika Rittler 1, Eszter Molnár 1, Marcell Baranyi 1, Tamás Garay 2,3, József Tímár 1 and Balázs Hegedűs 1,4
1 Department of Pathology, Semmelweis University, Budapest, Hungary
2 Pázmány Péter Catholic University, Faculty of Information Technology and Bionics, Budapest, Hungary
3 Oncology Center, Semmelweis University, Budapest, Hungary
4 Department of Thoracic Surgery, Ruhrlandklinik, University Duisburg-Essen, Germany

Szekció

Pathology and Oncology I. Posters

Language of the presentation

Hungarian

Section, first choice

Pathology and Oncology

Section, second choice

Pharmaceutical Sciences

Összefoglaló szövege

Introduction
Oncogenic mutations in the RAS/RAF and RAS/PI3K pathways play an important role in carcinogenesis and maintenance of tumors. The direct targeting of mutant BRAF as monotherapy has limited efficacy due to acquired resistance, therefore combination is inevitable in targeted therapy. Often additional pathways are affected by mutations, however, it is not clear whether these mutations predict the impact of the combined inhibition of the corresponding pathways.
Aims
In our study, we aimed to determine the effectiveness of the horizontal combined inhibition of the RAS/RAF and the RAS/PI3K pathways in BRAF mutant cells with or without oncogenic mutations in the PI3K pathway.
Method
Selumetinib and BEZ235 were tested alone and in combination on eight BRAF mutant human cancer cell lines (melanoma, lung and colon) including five with mutations in the PI3K pathway. To assess the effect of these inhibitors on cell lines, short term cell viability, long term colony formation and protein expression examination were performed via SRB assay, clonogenic assay and western blot, respectively.
Results
Selumetinib was more effective on BRAF mutant cell lines compared to cells with BRAF and concomitant mutations from the PI3K/Akt pathway, especially in short term examinations. In contrast, BEZ did not show strong mutation-specific effect on the cells. Combinations of these inhibitors had synergistic effect in a few cell lines based on combination index. BEZ and selumentinib decreased p-S6 and p-Erk levels upon treatment, respectively. Combination treatment either resulted in similar effect or increased the phosphorylation of these proteins. Interestingly, p-Akt level decreased upon treatment with BEZ and especially with selumetinib plus BEZ only in the cell line with highest sensitivity against combination therapy.
Conclusion
These results show that combination therapy can be more effective than single treatment in certain cases. Furthermore, decrease of Akt activation upon combination treatment in the most sensitive cell line suggests that Akt activation may have a key role in the sensitivity for this combinational treatment. However, further investigations are warranted to find predictive markers for effective treatment combinations.

Additional Information

Doctoral School of Pathological Sciences
Oncology
Supervisor: Balázs Hegedűs
rittlerdomi@gmail.com

Bemutatás módja

Poszter

Kind

Szabad

Status

elfogadva

Accepted presentation method

poszter

Előadás fájl jóváhagyás

nem rendelkezett róla

Előadó

2883

Start

11:20

End

11:23

Authors (legacy)

Dominika Rittler 1, Eszter Molnár 1, Marcell Baranyi 1, Tamás Garay 2,3, József Tímár 1 and Balázs Hegedűs 1,4
1 Department of Pathology, Semmelweis University, Budapest, Hungary
2 Pázmány Péter Catholic University, Faculty of Information Technology and Bionics, Budapest, Hungary
3 Oncology Center, Semmelweis University, Budapest, Hungary
4 Department of Thoracic Surgery, Ruhrlandklinik, University Duisburg-Essen, Germany