Title: New therapeutic strategy to specifically target the oncogenic function of eukaryotic translation initiation factor 4A1
Funder: Cancer Research UK

Abstract: Background Non-small cell lung cancer (NSCLC) is one of CRUK cancers of unmet need based on current treatment strategies and survival rates. In NSCLC and other cancers, tumourigenesis is driven by an oncogenic translational programme establishing an oncogenic proteome. Eukaryotic translation initiation factor 4A1 (eIF4A1), a key protein in translation initiation, is commonly overexpressed in many cancers including NSCLC, correlating with poor prognosis. Oncogenic mRNAs contain substantial RNA structures requiring unwinding for translation. eIF4A1 resolves these structures which drives the oncogenic translational programme. Importantly, downregulation of eIF4A1 reduces tumour growth. Therefore, there is substantial interest to target eIF4A1 therapeutically. However, natural eIF4A1-inhibitors, and derivatives thereof, show critical toxicity in animal models and are not suited for human application. As eIF4A1 has a second activity in mRNA-loading onto ribosomes, required for normal cell function, it has been suggested that these compounds inhibit not only oncogenic eIF4A1 unwinding but also vital eIF4A1 functions in mRNA-loading. We have discovered a novel molecular mechanism that regulates eIF4A1 unwinding. This enables us to functionally separate its oncogenic activity from its other vital functions. We found that eIF4A1 forms monomeric and trimeric complexes upon RNA-binding and only the trimers show oncogenic activity in resolving RNA structures which suggests that eIF4A1-trimers are the main oncogenic driver. Aims We aim to understand how trimerisation regulates the oncogenic eIF4A1 unwinding and how natural eIF4A1-inhibitors function against eIF4A1-trimers to generate the knowledge that will propel the discovery of novel treatment strategies specifically targeting eIF4A1’s oncogenic function. The specific aims are: 1) Biochemical characterisation of the eIF4A1-trimerisation interface 2) Structural investigation of trimeric eIF4A1 3) Determination of the oncogenic translational programme delivered by trimeric eIF4A1 4) Development of an RNA unwinding assay to monitor the activity of the oncogenic trimeric eIF4A1 Methods 1) RNA unwinding/ATPase, RNA-binding, gel shift, analytical gel filtration 2) cryoEM, crystallography, HDX 3) RIP and CLIP seq, SILAC eIF4A1 has been implicated in many cancers, e.g. colorectal, haematological, melanoma and breast, based on its overexpression or role in translating key oncogenic proteins. Targeting eIF4A1 trimerisation, which is specifically required for its oncogenic unwinding capacity, offers the potential to generate more specific compounds that inhibit only the oncogenic eIF4A1 function. This may relieve toxicity seen with other eIF4A1-inhibitors leading to new therapies targeting translation in NSCLC and other cancers, and to new potential combination approaches, e.g. chemotherapy/radiotherapy and immune-oncology, as eIF4A1 supports a pro-survival response and translation of PDL1.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS