Abstract 2896: A genome-wide CRISPR/Cas9 pooled screen identifies EML4-ALK variant-specific synthetic lethal partners of HSP90 inhibitors

Abstract

Abstract The chromosomal rearrangement generating the EML4-ALK fusion protein occurs in 5–7% of patients with non-small-cell lung cancer (NSCLC). Distinct breakpoints give rise to variants with different EML4 fragments and an invariable ALK kinase domain. Patients treated with ALK tyrosine kinase inhibitors, such as crizotinib or alectinib, inevitably develop resistance to the drugs and need alternative therapies. EML4-ALK v1 and v3a/b, the most common variants of the fusion oncogene, display distinct cellular localization and different sensitivity to the inhibition of HSP90 chaperoning activity. In the clinic, HSP90 inhibitors have shown encouraging results in EML4-ALK+ NSCLC patients, but the responses have been heterogeneous. Currently, there is no EML4-ALK variant-based classification of patients and this might have contributed to confounding results in clinical trials. Moreover, the identification of additional biomarkers of sensitivity could further improve patient stratification and suggest potential combinatorial regimes. As chaperones are molecular hubs enriched for synthetic lethal partners, we performed a CRISPR/Cas9-based pooled screen in human NSCLC cell lines carrying different EML4-ALK variants in the presence of non-lethal concentrations of an HSP90 inhibitor. In the screen, we found already described as well as previously unreported EML4-ALK variant-specific synthetic lethal interactions. We are currently dissecting the mechanism behind these interactions, and evaluating their therapeutic potential for EML4-ALK+ NSCLC patients. Citation Format: Marco P. Licciardello, Paul A. Clarke, Paul Workman. A genome-wide CRISPR/Cas9 pooled screen identifies EML4-ALK variant-specific synthetic lethal partners of HSP90 inhibitors [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 2896.