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Ref Type Journal Article
PMID (28615361)
Authors Ross SJ, Revenko AS, Hanson LL, Ellston R, Staniszewska A, Whalley N, Pandey SK, Revill M, Rooney C, Buckett LK, Klein SK, Hudson K, Monia BP, Zinda M, Blakey DC, Lyne PD, Macleod AR
Title Targeting KRAS-dependent tumors with AZD4785, a high-affinity therapeutic antisense oligonucleotide inhibitor of KRAS.
Journal Vol Issue Date Pages Journal Short Title
Science translational medicine 9 394 2017 Jun 14 Sci Transl Med
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
AZD4785 AZD4785 0 1
Drug Name Trade Name Synonyms Drug Classes Drug Description
AZD4785 AZD-4785|AZD 785 Antisense Therapy 13 KRAS Inhibitor 15 AZD4785 is an antisense oligonucleotide targeting KRAS that results in the depletion of KRAS mRNA and protein, therefore leads to inhibition of tumor cell growth (PMID: 28615361).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References