Targeting KRAS dependent tumors with AZD4785, a high affinity therapeutic antisense oligonucleotide inhibitor of KRAS
AZD4785 is a therapeutic antisense oligonucleotide targeting KRAS mRNA with promising preclinical antitumor activity and a favorable safety profile. An antisensible approach to targeting KRAS Mutations that cause activation of the KRAS oncogene are common in human cancer, including treatment resistant tumor types such as lung and pancreatic cancer. KRAS has also proven to be notoriously difficult to target with small molecules. To overcome this issue, Ross et al. have turned to genetic technology, demonstrating an antisense oligonucleotide based therapy for inhibiting KRAS. The antisense oligonucleotide used in this study was chemically modified, allowing systemic delivery through subcutaneous injection and avoiding the need for a specialized delivery vehicle. The authors tested the efficacy of this therapy in multiple mouse models of non small cell lung cancer and evaluated its safety in primates, demonstrating its potential suitability for translation to humans. Activating mutations in KRAS underlie the pathogenesis of up to 20% of human tumors, and KRAS 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 KRAS mRNA. AZD4785 potently and selectively depleted cellular KRAS mRNA and protein, resulting in inhibition of downstream effector pathways and antiproliferative effects selectively in KRAS 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 KRAS mutant non small cell lung cancer cell line xenografts or patient derived xenografts resulted in inhibition of KRAS 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 KRAS driven human cancers and warrants further development.
Science Translational Medicine