Abstract PR12: Discovery and preclinical evaluation of cEt-modified KRAS antisense oligonucleotide inhibitors

Abstract

Abstract KRAS is one of the most frequently mutated genes in cancer and its activation is thought to underlie the pathogenesis of up to 30% of all human tumors. However, to date KRAS has proven difficult to target with traditional pharmacologic approaches. Antisense technology is particularly attractive for such difficult drug targets as antisense oligonucleotide (ASO) inhibitors can be designed based on a targets RNA sequence alone. cEt ASOs have been recently described and demonstrated to have significantly increased potency over previous generation ASO chemistries. Moreover, STAT3Rx/AZD9150, a cEt modified ASO targeting STAT3 mRNA was recently shown to produce robust STAT3 depletion in a broad range of xenograft models (AACR 2013) and importantly has also demonstrated promising single-agent antitumor activity in patients with advanced treatment-refractory cancers in phase I studies (ASCO 2013, EORTC 2014). Here, we describe the preclinical evaluation of potent and selective cEt ASOs targeted to human or mouse KRAS mRNA. A human-specific KRAS cEt ASO which potently and selectively down-regulated KRAS demonstrated anti-proliferative effects and the expected down-stream pathway inhibition in a panel of KRAS mutant NSCLC, CRC and PDAC cells. The KRAS ASO was differentiated from MAPK pathway inhibitors selectively inhibiting the proliferation of KRAS mutant not KRAS wild type cells and not causing feedback reactivation of the MAPK or PI3K pathways. Systemic delivery of the KRAS ASO to mice bearing KRAS mutant NSCLC or CRC xenografts resulted in significant inhibition of KRAS tumour expression and antitumor activity. Importantly, the KRAS ASO also showed significant target knockdown and antitumor effects in KRAS mutant NSCLC patient-derived xenografts (PDX). Finally, potent and selective murine-specific KRAS ASO produced robust target knockdown in a broad set of tissues without detectable tolerability signals associated with ASO-mediated systemic KRAS inhibition. Taken together these data suggest that KRAS ASOs are an attractive therapeutic approach to target KRAS for the treatment of human cancers. Citation Format: Alexey S. Revenko, Sarah J. Ross, Lyndsey L. Hanson, Rebecca Ellston, Chris May, Sanjay K. Pandey, Linda K. Buckett, Stephanie K. Klein, Mitchell Revill, Kevin Hudson, Brett P. Monia, David C. Blakey, Paul Lyne, Allan R. MacLeod. Discovery and preclinical evaluation of cEt-modified KRAS antisense oligonucleotide inhibitors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr PR12.