Oncogenic mutations in the KRAS gene are well-established drivers of cancer. 
While the recently developed KRASG12C inhibitors offer a targeted KRAS therapy 
and have shown success in the clinic, KRASG12C represents only 11% of all KRAS 
mutations. Current therapeutic approaches for all other KRAS mutations are both 
indirect and nonmutant-selective, largely focusing on inhibition of downstream 
KRAS effectors such as MAP kinases. Inhibition of KRAS downstream signaling 
results in a system-wide down-modulation of the respective targets, raising 
concerns about systemic cell toxicity. Here, we describe a custom short 
interfering RNA oligonucleotide (EFTX-D1) designed to preferentially bind mRNA 
of the most commonly occurring KRAS missense mutations in codons 12 and 13. We 
determined that EFTX-D1 preferentially reduced the mutant KRAS sequence versus 
wild-type at the levels of both transcription and translation and reversed 
oncogenic KRAS-induced morphologic and growth transformation. Furthermore, 
EFTX-D1 significantly impaired the proliferation of several KRAS mutant cancer 
cell lines in 2-D as well as 3-D assays. Taken together, our data indicate a 
novel use of RNA interference to target oncogenic KRAS-driven cancers 
specifically.