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Abstract Background: Y-box binding protein 1 (YB-1, YBX1) is a multifunctional nucleic acid binding protein that regulates the expression of various genes by binding to their mRNA and stabilizing them. In over 20 cancer types, including lung adenocarcinoma (LUAD), YBX1 expression is significantly elevated in tumor samples compared to normal tissue. Within cancer cells, YB-1 promotes the expression of genes involved in tumorigenesis and chemoresistance. Consequently, elevated YBX1 expression in tumor is associated with poor clinical outcomes and significantly reduced overall survival in LUAD patients. Therefore, YB-1 emerges as a promising therapeutic target for LUAD treatment. Utilizing a small molecule YB-1 inhibitor, CET056, we performed a series of in vitro and in vivo analyses to assess the therapeutic efficacy of YB-1 inhibition and unravel YB-1’s role in tumorigenesis and disease progression in LUAD. Methods: Four human and one mouse LUAD cell lines were treated with CET056 and/or chemotherapeutic drugs and analyzed for the in vitro therapeutic activity of CET056. Using xenograft and syngeneic LUAD mouse models, the preclinical therapeutic efficacy of CET056 on disease progression of LUAD was also tested. Results: CET056 was shown to effectively decrease YB-1 expression in both human and mouse LUAD cell lines and exert inhibitory effects on LUAD in vitro and in vivo. This treatment delayed tumor progression and metastasis in CMT-64 syngeneic mouse model. Proteomics analysis revealed that translational machinery-associated pathways were down-regulated in LUAD cells after CET056 treatment whereas apoptosis and cell death-associated pathways were up-regulated. In alignment with this finding, CET056 treatment in combination with cisplatin showed chemo-sensitizing effect on LUAD in vitro and in vivo. Conclusion: Our studies suggest that YB-1 could be a promising target for combating chemoresistance in LUAD. Inhibition of YB-1 with a small molecule drug as a monotherapy or combination therapy could an effective strategy to treat LUAD. Citation Format: Jee Min Lee, Dhanir Tailor, Fernando J. Garcia-Marques, Abel Bermudez, Sharon Pitteri, Sanjay V. Malhotra. Enhancing chemosensitivity of lung adenocarcinoma via Y-box binding protein 1 (YB-1) inhibition abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 668.
Lee et al. (Fri,) studied this question.