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Farnesyl-transferase inhibitors show synergistic anticancer effects in combination with novel KRAS-G12C inhibitors

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Titel: Farnesyl-transferase inhibitors show synergistic anticancer effects in combination with novel KRAS-G12C inhibitors
Autoren: Marcell Baranyi, Eszter Molnár, Luca Hegedűs, Zsófia Gábriel, Flóra Gréta Petényi, Fanni Bordás, Violetta Léner, Ivan Ranđelović, Mihály Cserepes, József Tóvári, Balázs Hegedűs, József Tímár
Quelle: Br J Cancer
Verlagsinformationen: Springer Science and Business Media LLC, 2024.
Publikationsjahr: 2024
Schlagwörter: 0301 basic medicine, 0303 health sciences, Lung Neoplasms, Medizin, Adenocarcinoma of Lung, Adenocarcinoma, Article, 3. Good health, Adenocarcinoma of Lung [MeSH], Pancreatic Neoplasms/genetics [MeSH], Mutation [MeSH], Humans [MeSH], Lung Neoplasms/genetics [MeSH], Colorectal Neoplasms/drug therapy [MeSH], Animals [MeSH], Pancreatic Neoplasms/drug therapy [MeSH], 631/67/1612, Proto-Oncogene Proteins p21(ras)/genetics [MeSH], Enzyme Inhibitors/pharmacology [MeSH], Adenocarcinoma/drug therapy [MeSH], Adenocarcinoma/genetics [MeSH], Transferases [MeSH], 631/67/1504, Colorectal Neoplasms/genetics [MeSH], 631/67/1059, Lung Neoplasms/drug therapy [MeSH], Disease Models, Animal [MeSH], article, Pancreatic Neoplasms, Proto-Oncogene Proteins p21(ras), Disease Models, Animal, 03 medical and health sciences, Transferases, Mutation, Humans, Animals, Enzyme Inhibitors, Colorectal Neoplasms
Beschreibung: Background Inhibition of mutant KRAS challenged cancer research for decades. Recently, allele-specific inhibitors were approved for the treatment of KRAS-G12C mutant lung cancer. However, de novo and acquired resistance limit their efficacy and several combinations are in clinical development. Our study shows the potential of combining G12C inhibitors with farnesyl-transferase inhibitors. Methods Combinations of clinically approved farnesyl-transferase inhibitors and KRAS G12C inhibitors are tested on human lung, colorectal and pancreatic adenocarcinoma cells in vitro in 2D, 3D and subcutaneous xenograft models of lung adenocarcinoma. Treatment effects on migration, proliferation, apoptosis, farnesylation and RAS signaling were measured by histopathological analyses, videomicroscopy, cell cycle analyses, immunoblot, immunofluorescence and RAS pulldown. Results Combination of tipifarnib with sotorasib shows synergistic inhibitory effects on lung adenocarcinoma cells in vitro in 2D and 3D. Mechanistically, we present antiproliferative effect of the combination and interference with compensatory HRAS activation and RHEB and lamin farnesylation. Enhanced efficacy of sotorasib in combination with tipifarnib is recapitulated in the subcutaneous xenograft model of lung adenocarcinoma. Finally, combination of additional KRAS G1C and farnesyl-transferase inhibitors also shows synergism in lung, colorectal and pancreatic adenocarcinoma cellular models. Discussion Our findings warrant the clinical exploration of KRAS-G12C inhibitors in combination with farnesyl-transferase inhibitors.
Publikationsart: Article
Other literature type
Sprache: English
ISSN: 1532-1827
0007-0920
DOI: 10.1038/s41416-024-02586-x
Zugangs-URL: https://pubmed.ncbi.nlm.nih.gov/38278976
https://repository.publisso.de/resource/frl:6518913
https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&origin=inward&scp=85183191581
https://doi.org/10.1038/s41416-024-02586-x
https://www.ncbi.nlm.nih.gov/pubmed/38278976
Rights: CC BY
Dokumentencode: edsair.doi.dedup.....5f26d2bf1668141270f4dd91e0b3537c
Datenbank: OpenAIRE
Beschreibung
Abstract:Background Inhibition of mutant KRAS challenged cancer research for decades. Recently, allele-specific inhibitors were approved for the treatment of KRAS-G12C mutant lung cancer. However, de novo and acquired resistance limit their efficacy and several combinations are in clinical development. Our study shows the potential of combining G12C inhibitors with farnesyl-transferase inhibitors. Methods Combinations of clinically approved farnesyl-transferase inhibitors and KRAS G12C inhibitors are tested on human lung, colorectal and pancreatic adenocarcinoma cells in vitro in 2D, 3D and subcutaneous xenograft models of lung adenocarcinoma. Treatment effects on migration, proliferation, apoptosis, farnesylation and RAS signaling were measured by histopathological analyses, videomicroscopy, cell cycle analyses, immunoblot, immunofluorescence and RAS pulldown. Results Combination of tipifarnib with sotorasib shows synergistic inhibitory effects on lung adenocarcinoma cells in vitro in 2D and 3D. Mechanistically, we present antiproliferative effect of the combination and interference with compensatory HRAS activation and RHEB and lamin farnesylation. Enhanced efficacy of sotorasib in combination with tipifarnib is recapitulated in the subcutaneous xenograft model of lung adenocarcinoma. Finally, combination of additional KRAS G1C and farnesyl-transferase inhibitors also shows synergism in lung, colorectal and pancreatic adenocarcinoma cellular models. Discussion Our findings warrant the clinical exploration of KRAS-G12C inhibitors in combination with farnesyl-transferase inhibitors.
ISSN:15321827
00070920
DOI:10.1038/s41416-024-02586-x