Determinants of EML4-ALK Driven Lung Cancer Growth and Therapeutic Responses
Worldwide Cancer Research
German Cancer Research Center
Lung adenocarcinomas (LUAD) in non-smokers often harbour specific genetic aberrations, such as gene fusions involving the Anaplastic Lymphoma Kinase (ALK) and the echinoderm microtubule-associated protein-like 4 (EML4). This oncogenic fusion has been reported to have 15 different variants, which harbour the same ALK sequence but differ in the EML4 breakpoint. Variant 1 and variant 3 differ greatly in the proportion of EML4 and are two most frequent oncogenic inversion in ALK-positive patients. Despite the development of second-and third-generation ALK inhibitors, patient responses are limited by drug resistance. In half of relapsed cases, resistance arises from secondary mutations in the TK domain; however, the mechanisms of resistance in patients lacking secondary mutations remain poorly characterized. Besides, the impact of concurrent genomic alterations in EML4-ALK driven tumours remains largely unknown. TP53 is mutated in 30% of ALK-rearranged LUAD and appears to be synergistic with variant 3, giving rise to more aggressive human disease. Despite the direct relevance to patient treatment, how these co-incident genomic alterations influence the robustness of therapeutic responses has never been investigated. Here we propose to employ state-of-the-art technologies and methodologies to model Eml4-Alk variants in vivo and study the tumour evolution and dynamics of the most aggressive variants (Aim1). In Aim 2, we will determine the impact of co-incident genomic alterations on EML4-ALK-driven lung cancer development, by inactivating putative tumour suppressor genes in a variant-specific manner. Finally, in Aim 3, we will determine the impact of different Eml4-Alk variants and concomitant genomic alterations on response to ALK inhibition. By combining multiplex genome editing with drug treatment, we will perform the equivalent of hundreds of genotype-directed clinical trials in parallel and therefore this project will have a direct impact on personalised treatment for patients with EML4-ALK lung tumours.
2.1 Biological and endogenous factors