Inhibition of protein translational machinery in triple-negative breast cancer as a promising therapeutic strategy

Arpit Dheeraj; Fernando Jose Garcia Marques; Dhanir Tailor; Abel Bermudez; Angel Resendez; Mallesh Pandrala; Benedikt Grau; Praveen Kumar; Carrsyn B Haley; Alexander Honkala; Praveen Kujur; Stefanie S Jeffrey; Sharon Pitteri; Sanjay V Malhotra

doi:10.1016/j.xcrm.2024.101552

Inhibition of protein translational machinery in triple-negative breast cancer as a promising therapeutic strategy

Cell Rep Med. 2024 May 21;5(5):101552. doi: 10.1016/j.xcrm.2024.101552. Epub 2024 May 9.

Affiliations

¹ Department of Cell, Developmental and Cancer Biology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA; Center for Experimental Therapeutics, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA; Department of Radiation Oncology, Stanford University School of Medicine, Palo Alto, CA, USA.
² Department of Radiology, Canary Center at Stanford for Cancer Early Detection, Stanford University School of Medicine, Palo Alto, CA, USA.
³ Department of Radiation Oncology, Stanford University School of Medicine, Palo Alto, CA, USA.
⁴ Department of Cell, Developmental and Cancer Biology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA; Center for Experimental Therapeutics, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
⁵ Center for Experimental Therapeutics, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
⁶ Department of Surgery, Stanford University School of Medicine, Palo Alto, CA, USA.
⁷ Department of Cell, Developmental and Cancer Biology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA; Center for Experimental Therapeutics, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA; Department of Radiation Oncology, Stanford University School of Medicine, Palo Alto, CA, USA. Electronic address: [email protected].

Abstract

Y-box binding protein-1 (YB-1) is a proto-oncogenic protein associated with protein translation regulation. It plays a crucial role in the development and progression of triple-negative breast cancer (TNBC). In this study, we describe a promising approach to inhibit YB-1 using SU056, a small-molecule inhibitor. SU056 physically interacts with YB-1 and reduces its expression, which helps to restrain the progression of TNBC. Proteome profiling analysis indicates that the inhibition of YB-1 by SU056 can alter the proteins that regulate protein translation, an essential process for cancer cell growth. Preclinical studies on human cells, mice, and patient-derived xenograft tumor models show the effectiveness of SU056. Moreover, toxicological studies have shown that SU056 treatment and dosing are well tolerated without any adverse effects. Overall, our study provides a strong foundation for the further development of SU056 as a potential treatment option for patients with TNBC by targeting YB-1.

Keywords: CETSA; RPL; RPS; YB-1; eIF; protein translation; proteosome profiling; ribosomes; small molecule; triple-negative breast cancer.

MeSH terms

Animals
Cell Line, Tumor
Cell Proliferation / drug effects
Female
Gene Expression Regulation, Neoplastic / drug effects
Humans
Mice
Mice, Nude
Protein Biosynthesis* / drug effects
Triple Negative Breast Neoplasms* / drug therapy
Triple Negative Breast Neoplasms* / metabolism
Triple Negative Breast Neoplasms* / pathology
Xenograft Model Antitumor Assays*
Y-Box-Binding Protein 1* / genetics
Y-Box-Binding Protein 1* / metabolism

Substances

Y-Box-Binding Protein 1
YBX1 protein, human