Abstract 4479: Targeting of eIF4A1 curtails lung metastases in triple-negative breast cancer

Abstract

Abstract Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer. Patients diagnosed with TNBC benefit less or none from any current targeted therapies and also the standard-of-care neoadjuvant chemotherapies (NACT) which is cytotoxic. TNBC shows an increased risk of tumor relapse, therapy failure, and high proclivity to develop distant metastases. Intrinsic resistance to NACT is mainly due to a small population of breast cancer cells that acquire stem cell-like features (BCSCs). BCSCs are capable of self-renewal, proliferation, plasticity, immune regulation and chemoresistance. These properties mediate tumorigenesis, metastasis, and resistance to NACT and sometimes even to targeted therapy. Overall, FDA-approved drugs that are effective for advanced TNBC are currently unavailable. The eukaryotic translation initiation factor (eIF4A1) is an mRNA helicase that catalyzes the ATP-dependent unwinding of many oncogenic mRNAs which harbor secondary structures in the 5’ leader region. There is preferential reliance on eIF4A1 by tumor cells as many oncogenic mRNAs require the helicase activity of eIF4A1 for their efficient translation. Several eIF4A1-dependent mRNAs (downstream effectors) include: survivin (survival), c-MYC, STAT1 (immunoevasion through transcription and subsequent translation of PD-L1), Rho kinase1 (invasion), and Cyclins D1 and D3. Bioinformatic analyses revealed that higher gene expression of eIF4A1 significantly impacts patient survival. Clinically, an enhanced protein expression of eIF4A1 was evident in histopathologic analyses of drug-resistant human TNBC biospecimens. Importantly, our in vitro data indicated that the viability of BCSCs was significantly reduced when eIF4A1 is targeted by nanomolar levels of Rocaglamide A (RocA). Furthermore, in paclitaxel-resistant TNBC cells, there is an upregulation in the total levels of eIF4A1 and its downstream effectors. Pluripotency transcription factors (e.g., SOX2, OCT4 and NANOG) and drug transporters (ABCB1, ABCG2 and ABCC1) were also increased in an eIF4A1-dependent manner. Genetic ablation and pharmacological targeting of eIF4A1 with RocA reversed the drug-resistant profile. Our in vitro data implied a key role for eIF4A1 in chemoresistance/therapy failure. Targeting of eIF4A1 may be an effective anti-cancer strategy to overcome drug resistance. To this end, we orthotopically implanted CRISPR-control (CC) and eIF4A1-KO (KO) human TNBC cells and evaluated the primary tumor progression and metastases in NOD/SCID-beige mice. Longitudinal tumor progression was followed by IVIS imaging. The tumor volume and the wet weight was significantly higher in CC than KO tumors (n=7 mice). Similarly, the lung metastatic burden is significantly low in KO than CC mice (n=7 mice; p<0.002)). Taken together, we propose that eIF4A1 is an actionable molecular target for drug-resistant TNBC using chemotherapy/immunotherapy. Citation Format: Sangita Sridharan, Shobhit Srivastava, David Terrero, Saloni Malla, Amit K. Tiwari, Dayanidhi Raman. Targeting of eIF4A1 curtails lung metastases in triple-negative breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4479.