One of the mechanisms potentially explaining the discrepancy between the number of
human genes and the functional complexity of organisms is generating alternative splice
variants, an attribute of the vast majority of multi-exon genes. Members of the RAS
family, such as NRAS, KRAS and HRAS, all of which are of significant importance in
cancer biology, are no exception. The structural and functional differences of these
splice variants, particularly if they contain the canonical (and therefore routinely
targeted for diagnostic purposes)hot spotmutations, pose a significant challenge for
targeted therapies. We must therefore consider whether these alternative splice variants
constitute a minor component as originally thought and how therapies targeting the
canonical isoforms affect these alternative splice variants and their overall functions.
