Unknown

Dataset Information

0

Silencing of Oncogenic KRAS by Mutant-Selective Small Interfering RNA.


ABSTRACT: 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.

SUBMITTER: Papke B 

PROVIDER: S-EPMC8033609 | biostudies-literature |

REPOSITORIES: biostudies-literature

Similar Datasets

| S-EPMC10582391 | biostudies-literature
| S-EPMC4694583 | biostudies-literature
| S-EPMC3908448 | biostudies-literature
| S-EPMC2828748 | biostudies-literature
| S-EPMC9305526 | biostudies-literature
| S-EPMC1951753 | biostudies-literature
| S-EPMC2693358 | biostudies-literature
| S-EPMC8258458 | biostudies-literature
| S-EPMC7163449 | biostudies-literature
| S-EPMC7092946 | biostudies-literature