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

Abstract

Activating mutations in underlie the pathogenesis of up to 20% of human tumors, and 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 mRNA. AZD4785 potently and selectively depleted cellular mRNA and protein, resulting in inhibition of downstream effector pathways and antiproliferative effects selectively in 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 mutant non-small cell lung cancer cell line xenografts or patient-derived xenografts resulted in inhibition of 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-driven human cancers and warrants further development.

Rac1 activates non-oxidative pentose phosphate pathway to induce chemoresistance of breast cancer

“…Rac1 is a member of the small guanosine triphosphatases (GTPases), which was considered "hard-to-target" despite numerous efforts to develop GTPase inhibitors 35 . Recently, targeting mRNA instead of protein by antisense or siRNA oligonucleotides has become an alternative strategy to target GTPase for cancer treatment 36,37 . However, siRNAs, the polyanionic biomacromolecules, are easily attacked by serum nucleases and cannot readily cross the cell membrane.…”

Antisense STAT3 inhibitor decreases viability of myelodysplastic and leukemic stem cells

“…AZD9150 is rapidly incorporated by primary MDS/AML stem and progenitor cells and leads to STAT3 inhibition. The increased potency of generation 2.5 ASOs over previous ASO chemistries enables the delivery of a sufficient amount of ASO to cells in culture or in vivo without the need for any type of delivery vehicle (9,18). Thus, we evaluated the ability of AZD9150 formulated in saline to be incorporated by primary stem and progenitor cells.…”

Transcription and Translation Inhibitors in Cancer Treatment

“…Another ASO that has shown promising results was AZD4785. AZD4785 is a cET-ASO targeting KRAS (Ross et al, 2017), an oncogene that is often mutated in association with cancer. AZD4785 was previously shown to efficiently deplete KRAS and was associated with an antitumor effect in mice (Ross et al, 2017;Sacco et al, 2019).…”

“…AZD4785 is a cET-ASO targeting KRAS (Ross et al, 2017), an oncogene that is often mutated in association with cancer. AZD4785 was previously shown to efficiently deplete KRAS and was associated with an antitumor effect in mice (Ross et al, 2017;Sacco et al, 2019). In addition, cellular trafficking and localization of AZD4785 across different tumor cell lines have been characterized and was found to vary (Linnane et al, 2019).…”