SNPD-siKRAS: siRNA specifically inhibits KRAS with a single-nucleotide mutation

Abstract

Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) is the most frequently mutated gene associated with pancreatic cancer. However, targeting mutated KRAS without affecting the wild-type KRAS expression by conventional chemotherapy is challenging, because KRAS protein is considered to be undruggable due to the lack of surface structures for drug binding. Here, we developed a single-nucleotide polymorphism-distinguishable small interfering RNA (SNPD-siRNA) that suppresses the expression of mutated KRAS without affecting the wild type KRAS expression through discrimination of single-nucleotide differences using RNA interference technology. In two- and three-dimensional cultures of human pancreatic cancer-derived cell lines, SNPD-siKRAS significantly reduced the mutated KRAS expression, and suppressed the cell proliferation by inhibiting the activity of MAPK/PI3K pathway. Furthermore, the xenograft experiments using mice revealed that the growth of implanted pancreatic cancer-derived cells were suppressed by the SNPD-siKRAS. Thus, this technology may provide a therapeutic platform for personalized genomic medicine that can identify the single nucleotide mutations in the disease-causing genes.