Characterization of off-target effects of a first-in-class EGFR-directed KRAS G12V selective inhibitor, EFTX-G12V, in SKCO1 cells.

Despite KRAS-G12V being the second most common KRAS mutation in cancer, there are no approved direct KRAS-G12V inhibitors. Difficulties with inhibiting oncogenes using conventional approaches have prompted the use of RNAi as a therapeutic approach. RNAi has faced numerous obstacles as a cancer therapeutic, including the lack of cancer-specific tissue targeting, rapid oligonucleotide nuclease degradation and clearance from the circulation. Recently, the use of targetable ligands conjugated to chemically modified siRNAs has shown remarkable promise in circumventing these barriers. We demonstrate that EFTX-G12V is highly selective for KRAS-G12V and has improved therapeutic activity over pan-KRAS targeting, including enhanced inhibition of several cancer hallmarks. With a novel RNAi delivery platform, we demonstrate tumor silencing of KRAS-G12V and significant anti-tumor activity across several cancer models. Our findings represent a technologic advance in oncogene targeting using RNAi and reveal new biologic insights in KRAS targeting that may have broad implications with regards to safety and efficacy. This dataset collects the RNA-Seq data for the SKCO1 cell line.