Reference Detail

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 Science translational medicine
Vol 9
Issue 394
Date 2017 Jun 14
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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Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Therapy Description
AZD4785 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).
Drug Name Trade Name Synonyms Drug Classes Drug Description
AZD4785 Antisense Therapy 1 KRAS Inhibitor 2 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).
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
KRAS mutant lung carcinoma sensitive AZD4785 Preclinical - Cell line xenograft Actionable In a preclinical study, AZD4785 inhibited Kras expression, resulted in growth inhibition in 3-D cultures of lung carcinoma cell lines harboring KRAS mutations, and anti-tumor activity in cell line xenograft models (PMID: 28615361). 28615361
KRAS G13D non-small cell lung carcinoma sensitive AZD4785 Preclinical - Cell line xenograft Actionable In a preclinical study, AZD4785 inhibited Kras expression, resulted in growth inhibition in 3-D cultures of non-small cell lung carcinoma cells harboring KRAS G13D, and anti-tumor activity in cell line xenograft models (PMID: 28615361). 28615361
KRAS wild-type non-small cell lung carcinoma decreased response AZD4785 Preclinical - Pdx Actionable In a preclinical study, AZD4785 inhibited Kras expression in tumors, but had no effect on tumor growth in patient-derived xenograft models of KRAS wild-type non-small cell lung carcinoma (PMID: 28615361). 28615361
KRAS Q61H non-small cell lung carcinoma sensitive AZD4785 Preclinical - Cell culture Actionable In a preclinical study, AZD4785 inhibited Kras expression, resulted in growth inhibition in 3-D cultures of non-small cell lung carcinoma cell lines harboring KRAS Q61H (PMID: 28615361). 28615361
KRAS wild-type colorectal cancer decreased response AZD4785 Preclinical - Cell culture Actionable In a preclinical study, KRAS wild-type colorectal cancer cell lines demonstrated decreased respond to AZD4785 compared to KRAS mutant cell lines in culture (PMID: 28615361). 28615361
KRAS G12V colorectal cancer sensitive AZD4785 Preclinical - Cell culture Actionable In a preclinical study, AZD4785 inhibited Kras expression, resulted in growth inhibition in 3-D cultures of colorectal cancer cell lines harboring KRAS G12V (PMID: 28615361). 28615361
KRAS G12D pancreatic cancer sensitive AZD4785 Preclinical - Cell culture Actionable In a preclinical study, AZD4785 inhibited Kras expression, resulted in growth inhibition in 3-D cultures of pancreatic cancer cells harboring KRAS G12D (PMID: 28615361). 28615361
KRAS G12C lung cancer sensitive AZD4785 Preclinical - Pdx Actionable In a preclinical study, AZD4785 inhibited Kras expression and downstream signaling, resulted in tumor growth inhibition in patient-derived xenograft models of lung cancer harboring KRAS G12C (PMID: 28615361). 28615361
KRAS wild-type lung carcinoma decreased response AZD4785 Preclinical - Cell culture Actionable In a preclinical study, KRAS wild-type lung carcinoma cell lines demonstrated decreased respond to AZD4785 compared to KRAS mutant cell lines in culture (PMID: 28615361). 28615361
KRAS G12S lung carcinoma sensitive AZD4785 Preclinical - Cell culture Actionable In a preclinical study, AZD4785 inhibited Kras expression, resulted in growth inhibition in 3-D cultures of lung carcinoma cells harboring KRAS G12S (PMID: 28615361). 28615361
KRAS G12C non-small cell lung carcinoma sensitive AZD4785 Preclinical - Cell line xenograft Actionable In a preclinical study, AZD4785 inhibited Kras expression, resulted in growth inhibition in 3-D cultures of non-small cell lung carcinoma cell lines harboring KRAS G12C, and anti-tumor activity in cell line xenograft models (PMID: 28615361). 28615361