A First-in-Class EGFR-Directed KRAS G12V Selective Inhibitor
Description
Despite KRASG12V being the 2nd most common KRAS mutation in cancer, there are no approved direct KRASG12V inhibitors. Difficulties with inhibiting oncogenes using conventional approaches have prompted 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 circulation. Recently, the use of targetable ligands conjugated to chemically modified siRNAs have shown remarkable promise in circumventing these barriers. We demonstrate EFTX-G12V is highly selective for KRASG12V and has improved therapeutic activity over pan-KRAS targeting, including enhanced inhibition of several cancer hallmarks. With a targeted RNAi delivery platform, we demonstrate tumor silencing of KRASG12V, and significant anti-tumor activity across several cancer models. Our findings represent a technological advance in oncogene targeting using RNAi and reveal new biologic insights in KRAS targeting that may have broader implications with regards to safety and efficacy.