Abstract B05: ASN007, an oral ERK1/2 inhibitor, shows strong antitumor activity across a panel of KRAS subtype mutant cancer models

Abstract

Abstract The RAS/MAPK pathway is one of the most commonly dysregulated signaling pathways found in human cancers. KRAS, HRAS and NRAS genes, which play a critical role in transducing the signal from receptor tyrosine kinases to the downstream target proteins such as BRAF and MEK1/2, are frequently mutated in most solid tumors. The extracellular signal-regulated kinases, ERK1 and ERK2 (ERK1/2), which are downstream of MEK and RAF kinases, serve as a key node in this crucial signaling pathway in tumor cells. Targeting ERK1/2 offers a promising therapeutic strategy for a broad range of cancers, particularly the ones driven by RAS mutations, and in overcoming resistance to MEK/BRAF inhibitors. In this report, we present discovery and characterization of a novel orally bioavailable compound, ASN007, that showed potent inhibition of ERK1/2 kinases in a biochemical assay with IC50 = 2 nM for both targets. Interestingly, ASN007 displayed a much slower dissociation rate (longer target residence time) as compared to other ERK inhibitors. ASN007 showed potent antiproliferative activity that was selective for RAS/MAPK pathway dependent cancer cell lines, and did not affect the growth of cell lines harboring PI3K pathway or receptor tyrosine kinase mutations. Of note, ASN007 showed much more potent and broader activity against a panel of RAS mutant cell lines as compared to other ERK1/2 inhibitors. In a panel of 96 KRAS mutant cell lines, ASN007 showed strong activity across all KRAS subtype mutations, including G12C, G12D, G12V and G13D. In tumor xenograft models harboring KRAS and NRAS mutations, a daily oral dosing regimen of ASN007 provided strong tumor growth inhibition and was well tolerated. ASN007 also showed strong single-agent antitumor activity in colorectal PDX models with various KRAS subtype mutations including G12C, G12D, and G12S. A clinical phase 1 trial of ASN007 in patients with BRAF and KRAS, HRAS and NRAS mutant melanoma, colorectal, non-small lung and pancreatic cancers is currently ongoing (NCT03415126). Citation Format: Sanjeeva P. Reddy, Scott K. Thompson, Helen Usansky, Roger A. Smith, Louis Denis, Sandeeep Gupta. ASN007, an oral ERK1/2 inhibitor, shows strong antitumor activity across a panel of KRAS subtype mutant cancer models [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr B05.