Abstract 158: ASN003, a highly selective inhibitor of B-Raf and PI3 kinases, shows strong antitumor activity in B-Raf inhibitor resistant patient-derived xenograft models
Authors: Thompson Scott K. , Smith Roger A. , Rao Niranjan , Wick Michael J. , Reddy Sanjeeva P. 
Published: July 2017

Abstract
The RAS-RAF-MEK and PI3K-AKT-mTOR pathways are two major signaling pathways involved in human cancer. Components of these two pathways are frequently mutated in a wide variety of solid tumors. Concurrent double mutations in the two pathways are also observed quite often in a broad range of tumor types. Additionally, inhibition of one of these pathways often leads to the upregulation of the other pathway and development of resistance. In preclinical models, combined inhibition of both pathways has been shown to impart greater efficacy as compared to inhibition of either pathway alone. ASN003 is a novel, highly selective, small-molecule inhibitor of both RAS-RAF and PI3K pathways, discovered using a rational design approach. ASN003 shows potent inhibitory activity against B-RAF and PI3K kinases (low nM IC50). Within the PI3K family, ASN003 has high selectivity for inhibition of PI3Kα and PI3Kδ over PI3Kβ. In a panel of 292 kinases, ASN003 showed high selectivity for inhibiting B-RAF and PI3 kinases, and associated mutant kinases. In cell-based mechanistic studies, ASN003 inhibited phosphorylation of ERK, AKT and S6, and showed strong antiproliferative activity (IC50 = 60-300 nM) in cell lines with B-RAF and PI3K pathway mutations as well as in vemurafenib-resistant cell lines. In pharmacodynamic studies in multiple tumor models, ASN003 showed strong inhibition of the phosphorylation of downstream targets of B-RAF and PI3K, confirming appropriate target engagement. In in vivo efficacy studies, ASN003 showed strong tumor growth inhibition or regression in multiple tumor xenograft models, including A375 (B-Raf V600E mutation), RKO (B-Raf V600E and PIK3CA mutations), and A2058 (B-Raf V600E mutation and PTEN loss). We now report that ASN003 also showed strong tumor growth inhibition (&gt;80%) in a patient-derived xenograft (PDX) model established from a relapsed patient with progressive B-Raf mutant melanoma who showed initial response to vemurafenib. Sequencing analysis showed that the vemurafenib resistant tumor acquired a concurrent PIK3CA mutation. Dual targeting of the B-RAF and PI3K pathways with ASN003 has the potential to treat and/or prevent the acquired resistance to selective B-RAF inhibitors, and may also treat a broader patient population and provide greater efficacy and survival benefit than selective B-RAF inhibitors or selective PI3K pathway inhibitors alone. ASN003 is currently in Phase I clinical development in patients with advanced solid tumors, including tumors with B-Raf V600 mutation, PI3 kinase pathway alterations or PTEN loss.
Citation Format: Scott K. Thompson, Roger A. Smith, Niranjan Rao, Michael J. Wick, Sanjeeva P. Reddy. ASN003, a highly selective inhibitor of B-Raf and PI3 kinases, shows strong antitumor activity in B-Raf inhibitor resistant patient-derived xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 158. doi:10.1158/1538-7445.AM2017-158