K-Ras prenylation as a potential anticancer target.

Cancer Metastasis Reviews
Marcell BaranyiBalázs Hegedűs

Abstract

KRAS is one of the most commonly mutated oncogene and a negative predictive factor for a number of targeted therapies. Therefore, the development of targeting strategies against mutant KRAS is urgently needed. One potential strategy involves disruption of K-Ras membrane localization, which is necessary for its proper function. In this review, we summarize the current data about the importance of membrane-anchorage of K-Ras and provide a critical evaluation of this targeting paradigm focusing mainly on prenylation inhibition. Additionally, we performed a RAS mutation-specific analysis of prenylation-related drug sensitivity data from a publicly available database ( https://depmap.org/repurposing/ ) of three classes of prenylation inhibitors: statins, N-bisphosphonates, and farnesyl-transferase inhibitors. We observed significant differences in sensitivity to N-bisphosphonates and farnesyl-transferase inhibitors depending on KRAS mutational status and tissue of origin. These observations emphasize the importance of factors affecting efficacy of prenylation inhibition, like distinct features of different KRAS mutations, tissue-specific mutational patterns, K-Ras turnover, and changes in regulation of prenylation process. Finally, ...Continue Reading

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Citations

Aug 12, 2020·Veterinary and Comparative Oncology·Kosuke KobayashiMasaru Okuda
Jul 31, 2020·Cancer Metastasis Reviews·Robin A Weiss
Jan 14, 2021·Cell Chemical Biology·Ruth NussinovVadim Gaponenko
Apr 25, 2021·Breast Cancer Research and Treatment·Anjana BhardwajIsabelle Bedrosian
May 6, 2021·Journal of Nanobiotechnology·Lynn N JenaHelen O McCarthy
Jul 3, 2021·Cancers·Hyuk Moon, Simon Weonsang Ro
Jan 28, 2022·Expert Opinion on Drug Discovery·Kashif HaiderAhmed Kamal

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Methods Mentioned

BETA
GTPases
geranylgeranylation
GTPase
xenograft
glycosylation

Clinical Trials Mentioned

NCT03496766
NCT02383927
NCT03719690
NCT00005648

Software Mentioned

Graphpad Prism
PRISM

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