Abstract A42: Sensitivity and resistance to a p-AKT inhibitor in an erlotinib-sensitive model for lung cancer

Abstract

Abstract Activating mutations in EGFR, such as the L858R mutation, are effective predictors of response to EGFR tyrosine kinase inhibitor (TKI) therapy. While most patients initially respond to EGFR TKIs, the majority relapse within 6-12 months, underscoring the importance of identifying therapies that enhance and prolong EGFR TKI activity in patients. Agents targeting additional nodes in the EGFR pathway have the potential to overcome such resistance but single-agent activity must be understood first. We utilized mice engineered to develop erlotinib-sensitive lung adenocarcinomas driven by the human EGFR L858R mutation to evaluate the efficacy of a p-AKT inhibitor, MK-2206, currently in clinical trials for a variety of solid tumor malignancies. MK-2206 concentration and target activity were assessed in short-term PK/PD studies in both the lungs and blood of tumor-bearing mice. MK-2206 was then evaluated in an efficacy study using a twice-weekly dosing regimen, both as a single agent and in combination with other TKIs. MK-2206 alone resulted in tumor regression or tumor growth inhibition in ∼50% of the mice, but exhibited greater efficacy in combination with other upstream pathway inhibitors. Temporal evaluation of tumor growth inhibition indicated that MK-2206 was most effective at early time points and did not produce a sustained pathway and growth response as treatment continued. Analysis of gene expression changes in mice treated with MK-2006 alone vs. MK-2206 in combination with EGFR TKIs highlighted the pathways perturbed by both drugs.