Abstract B30: Novel targets for combination therapy in EGFR mutated NSCLC

Abstract

Abstract Non-small cell lung cancer (NSCLC) patients with activating mutations in the epidermal growth factor receptor (EGFR) gene generally show good responses to therapy with EGFR tyrosine kinase inhibitors (EGFR-TKIs). Unfortunately resistance emerges during treatment, driven by different mechanisms. Mutation-driven mechanisms are becoming well understood and include secondary mutations in the EGFR (T790M for 1st generation EGFR-TKIs and C797S for 3rd generation EGFR-TKIs) and activating mutations in NRAS. On the other hand, non-mutation based resistance mechanisms are less well understood but may involve activation of alternative, potentially targetable signalling pathways. To identify alternative signalling pathways and potential combination targets, we performed a bioactive small molecule (n=1902) screen to identify targets that could delay the emergence of resistance to sustained inhibition of EGFR in EGFR-mutant NSCLC cells. 9 out of 186 target classes were significantly enriched (p< 0.05) within the top 2.5 % of screen compounds, when ranked for their ability to sensitise cells to the 3rd generation EGFR-TKI AZD9291. We identified expected hits such as AKT, PI3K and mTOR but also novel targets. To prioritise targets for in vivo validation, compounds were tested in 3D-spheroids, which have a complex microenvironment, providing a more tumour-like model. Most compounds were more cytotoxic in 3D compared to 2D when used individually, preventing or slowing down spheroid growth. EGFR-TKI combination effects in 3D varied when compared to 2D-models. FAK inhibition was less effective in spheroids compared to 2D. AKT or MEK inhibitors showed marked effects in combination, further delaying spheroid growth under EGFR-TKI treatment but also inhibited spheroid growth when used on their own. Inhibitors of novel targets were identified that showed promising combination effects even at sub-toxic single-agent doses. Our data identify new candidates for combination therapy with EGFR-TKIs and suggest that 3D-spheroids may be a useful approach for prioritising combinations for in vivo studies. Citation Format: Neele Drobnitzky, Agata Patel, Amalina Mumin, Fiona Cahill, Luiza Madia Lourenco, Samantha Olyha, Sureyya Corbacioglu, Yanyan Jiang, Anderson J. Ryan. Novel targets for combination therapy in EGFR mutated NSCLC [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr B30.