Targeting KRAS-dependent tumors with AZD4785, a high-affinity therapeutic antisense oligonucleotide inhibitor of KRAS.

Abstract

Activating mutations in <i>KRAS</i> underlie the pathogenesis of up to 20% of human tumors, and <i>KRAS</i> is one of the most frequently mutated genes in cancer. Developing therapeutics to block KRAS activity has proven difficult, and no direct inhibitor of KRAS function has entered clinical trials. We describe the preclinical evaluation of AZD4785, a high-affinity constrained ethyl-containing therapeutic antisense oligonucleotide (ASO) targeting <i>KRAS</i> mRNA. AZD4785 potently and selectively depleted cellular <i>KRAS</i> mRNA and protein, resulting in inhibition of downstream effector pathways and antiproliferative effects selectively in <i>KRAS</i> mutant cells. AZD4785-mediated depletion of KRAS was not associated with feedback activation of the mitogen-activated protein kinase (MAPK) pathway, which is seen with RAS-MAPK pathway inhibitors. Systemic delivery of AZD4785 to mice bearing <i>KRAS</i> mutant non-small cell lung cancer cell line xenografts or patient-derived xenografts resulted in inhibition of <i>KRAS</i> expression in tumors and antitumor activity. The safety of this approach was demonstrated in mice and monkeys with KRAS ASOs that produced robust target knockdown in a broad set of tissues without any adverse effects. Together, these data suggest that AZD4785 is an attractive therapeutic for the treatment of <i>KRAS</i>-driven human cancers and warrants further development.