Abstract 1053: A large cellular screen charting the landscape of synergistic drug combinations in lung cancer

Abstract

Abstract Introduction Non-small-cell lung cancer (NSCLC) is among the most common cancers, accounting for 85% of all lung cancer cases. Drug combinations are known to more effective than single drugs and can delay drug resistance. NSCLC has a poor prognosis and there are no approved targeted cancer drug combinations. Here we have conducted the first large-scale screen of drug combinations in NSCLC cell lines to identify new candidate synergistic combinations and map the landscape of synthetic lethal and synergistic pathways underlying them. Results We conducted the largest of its kind in vitro drug combination screening of 81 NSCLC cell-lines for 21 x 242 cancer drug combinations at 5 different doses. Our collection of approved and investigational drugs included mainly targeted drugs as well as some chemotherapy drugs. For each drug combination, we computed the synergy score using the Bliss model. Our key findings are as follows: 1. We identify drug combinations (like CHEK and WEE1 inhibitors) that are highly synergistic in many NSCLC cell lines. 2. Combinations of targeted therapies are overall more synergistic than chemotherapeutic drug combinations. 3. Synergistic combinations occur more within pathways. 4. We see that most drug combinations do not make cell lines more sensitive than the most sensitive cell line to the corresponding single agents across all the cell lines tested. 5. We identify a new class of drug combinations - called super-sensitizers - whose combined effects are larger than the effects observed for the individual drugs composing across all of the cohort cell-lines. 6. Combinations of multi-target drugs tend to be more synergistic than single-target drugs. 7. We identify and characterize a set of context-specific drug combinations that are differentially synergistic or differentially effective (i.e. viability after treatment) between wild-type vs mutant cell lines of various cancer drivers (KRAS, TP53, STK11, PIK3CA, EGFR). 8. Studying potential mechanistic underpinnings of drug synergism in NSCLC, we find that: (a) synergistic combinations target genes that have more proximal physical interactions, (b) some synergistic combinations target synthetic lethal combinations, (c) a subset of synergistic combinations have further support by NSCLC patients survival analysis. Conclusions We performed the first large in vitro drug combination screen in NSCLC. We identify top drug combinations that are highly synergistic and effective in many cell lines and characterize key biological properties and mechanisms underlying them. The screen results are provided in a user-friendly public data resource that can help facilitate the development of targeted drug combinations in lung cancer therapy. Citation Format: Nishanth Ulhas Nair, Adam Friedman, Patricia Greninger, Avinash D. Sahu, Ellen Murchie, Giovanna Stein Crowther, Joe McClanaghan, Joo Sang Lee, Daniel A. Haber, Jeffrey Engelman, Eytan Ruppin, Cyril Benes. A large cellular screen charting the landscape of synergistic drug combinations in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1053.