Combination of the novel ERK inhibitor AZD0364 with the MEK inhibitor selumetinib significantly enhances antitumor activity in KRAS mutant tumor models

The RAS/MAPK pathway is a major driver in oncogenesis and is dysregulated in approximately 30% of human cancers, primarily by mutations in BRAF or RAS genes. While BRAF and MEK inhibitors improve BRAF mutant melanoma patient outcomes, single-agent pathway inhibitors have demonstrated limited clinical benefit. Therefore, combined inhibition of multiple nodes within the RAS/MAPK pathway may be necessary to effectively suppress pathway signaling and achieve meaningful clinical benefit, specifically in patients with KRAS mutant tumors. AZD0364 is a potent and highly selective inhibitor of ERK1 and ERK2. AZD0364 exhibits high cellular potency against a direct substrate (e.g., inhibition of phosphorylation of p90RSK in BRAF mutant A375 cells, IC 50 = 6 nM) and is highly (10/329 kinases tested are inhibited at u003e50% at 1 µM). In an unbiased cell proliferation screen of 750 tumor cell lines, u003e50% of cell lines that are sensitive to AZD0364 have RAS/MAPK pathway genetic alterations such as BRAF, NRAS or KRAS mutations. In a subset of KRAS mutant NSCLC cell lines, combined treatment of AZD0364 and selumetinib (AZD6244, ARRY-142886) is highly synergistic. This combination results in deeper and more durable suppression of the RAS/MAPK pathway that is not achievable with single-agent treatment, as assessed by phospho-p90RSK, change in transcriptional signatures and induction of apoptotic biomarkers. The AZD0364 and selumetinib combination also significantly suppresses RAS/MAPK pathway output and tumor growth in vivo to a greater extent than achievable with either agent given as a monotherapy. This combination is well tolerated in vivo and delivers 65% tumor regression in the NCI H358 KRAS mutant NSCLC xenograft model. This combination also results in significant tumor regressions in both A549 and HCT116 KRAS mutant xenografts. These data demonstrate that combined AZD0364 and selumetinib is well tolerated, effectively suppresses RAS/MAPK pathway signalling and delivers durable regressions in preclinical models. The combination of ERK and MEK inhibition represents a viable clinical approach to target KRAS mutant tumors. Citation Format: Vikki Flemington, Iain Simpson, Jason Breed, Emma Davies, Francis Gibbons, Phillip Hopcroft, Nicola Lyndsay, Christopher Jones, Clifford Jones, David Robinson, Claire Rooney, Karen Roberts, Linda Sandin, Richard Ward, Pei Zhang, Elizabeth Pease. Combination of the novel ERK inhibitor AZD0364 with the MEK inhibitor selumetinib significantly enhances antitumor activity in KRAS mutant tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1856.