AUTHOR=Molnár Eszter , Baranyi Marcell , Szigeti Krisztina , Hegedűs Luca , Bordás Fanni , Gábriel Zsófia , Petényi Gréta , Tóvári József , Hegedűs Balázs , Tímár József 

TITLE=Combination of farnesyl-transferase inhibition with KRAS G12D targeting breaks down therapeutic resistance in pancreatic cancer

JOURNAL=Pathology and Oncology Research

VOLUME=Volume 30 - 2024

YEAR=2024

URL=https://www.por-journal.com/journals/pathology-and-oncology-research/articles/10.3389/pore.2024.1611948

DOI=10.3389/pore.2024.1611948

ISSN=1532-2807

ABSTRACT=Pancreatic adenocarcinoma is one of the deadliest forms of cancer that lacks effective therapeutic options. KRAS mutation can be found in up to 90% of all pancreatic tumors, making it a promising therapeutic target. The introduction of new KRAS inhibitors has been a landmark in the history of KRAS mutant tumors, however, therapeutic resistance limits their efficacy. Thus, new therapeutic options, including combinational therapies, are urgently needed.Recently, we showed that KRAS G12C inhibitors in combination with farnesyl-transferase inhibitors exert synergistic antitumoral effects. Here, we provide evidence for the feasibility of this combinational approach to break down resistance in KRAS G12D mutant pancreatic cancer. Although we showed that the 3D environment dramatically sensitizes cells to MRTX1133 treatment, the synergistic effect of this drug combination is present both in 2D and 3D in the PANC1 pancreatic adenocarcinoma model, which showed high resistance towards MRTX1133 in 2D. Effects of the combinational treatment show an association with blockage of farnesylated regulatory proteins, including HRAS and RHEB, as well as with the expression level of KRAS. Our study warrants further investigation for the potential applicability of KRAS G12D inhibitors in combination with farnesyltransferase inhibitors for the treatment of KRAS mutant pancreatic adenocarcinoma.