Abstract

KRAS is one of the most frequently mutated genes in cancer and underlies the pathogenesis of up to 20% of human tumors. Developing therapeutics to block KRAS activity has proven difficult, and no direct inhibitor of KRAS function has entered clinical trials. AZD4785 is a high affinity cEt containing therapeutic antisense oligonucleotide (ASO) targeting KRAS. AZD4785 potently and selectively down-regulates KRAS mRNA and protein resulting in inhibition of down-stream effector pathways and proliferation selectively in KRAS mutant cells. Interestingly, AZD4785 mediated depletion of KRAS was not associated with feedback activation of the MAPK pathway, seen with RAS-MAPK pathway inhibitors. Systemic delivery of AZD4785 to mice bearing KRAS mutant NSCLC xenografts or patient-derived xenografts resulted in inhibition of KRAS tumor expression and anti-tumor 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. AZD4785 is being developed to treat KRAS dependent tumors including KRAS mutant lung cancer (NCT03101839).