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

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. EG...
Source: Molecular Cancer Therapeutics - Category: Cancer & Oncology Authors: Tags: Other Topics: Oral Presentations - Proffered Abstracts Source Type: research