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, we enlist the factors that might be responsible for the large discrepancy
between the outcomes in preclinical and clinical studies including methodological
pitfalls, the incomplete understanding of K-Ras protein turnover, and the variation
of KRAS dependency in KRAS mutant tumors.
