Targeting Phosphorylation of Y-Box-Binding Protein YBX1 by TAS0612 and Everolimus in Overcoming Antiestrogen Resistance

• Published in: Molecular cancer therapeutics 2020-03, Vol.19 (3), p.882-894
• Main Authors: Shibata, Tomohiro, Watari, Kosuke, Kawahara, Akihiko, Sudo, Tomoya, Hattori, Satoshi, Murakami, Yuichi, Izumi, Hiroto, Itou, Junji, Toi, Masakazu, Akiba, Jun, Akagi, Yoshito, Tanaka, Maki, Kuwano, Michihiko, Ono, Mayumi
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Apoptosis; Biomarkers, Tumor; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Proliferation; Drug Resistance, Neoplasm - drug effects; Drug Therapy, Combination; Estrogen Receptor Modulators - pharmacology; Everolimus - pharmacology; Female; Gene Expression Regulation, Neoplastic - drug effects; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Phosphorylation; Prognosis; Protein Kinase Inhibitors - pharmacology; Tumor Cells, Cultured; Xenograft Model Antitumor Assays; Y-Box-Binding Protein 1 - antagonists & inhibitors
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.mct-19-0690

Nuclear expression of Y-box-binding protein (YBX1) is closely correlated with clinical poor outcomes and drug resistance in breast cancer. Nuclear translocation of YBX1 is facilitated by YBX1 phosphorylation at serine 102 by AKT, p70S6K, and p90RSK, and the phosphorylated YBX1 (pYBX1) promotes expression of genes related to drug resistance and cell growth. A forthcoming problem to be addressed is whether targeting the phosphorylation of YBX1 overcomes antiestrogen resistance by progressive breast cancer. Here, we found that increased expression of pYBX1 was accompanied by acquired resistance to antiestrogens, fulvestrant and tamoxifen. Forced expression of YBX1/S102E, a constitutive phosphorylated form, resulted in acquired resistance to fulvestrant. Inversely, YBX1 silencing specifically overcame antiestrogen resistance. Furthermore, treatment with everolimus, an mTORC1 inhibitor, or TAS0612, a novel multikinase inhibitor of AKT, p70S6K, and p90RSK, suppressed YBX1 phosphorylation and overcame antiestrogen resistance and IHC analysis revealed that expression of pYBX1 and YBX1 was augmented in patients who experienced recurrence during treatment with adjuvant endocrine therapies. Furthermore, pYBX1 was highly expressed in patients with triple-negative breast cancer compared with other subtypes. TAS0612 also demonstrated antitumor effect against triple-negative breast cancer Taken together, our findings suggest that pYBX1 represents a potential therapeutic target for treatment of antiestrogen-resistant and progressive breast cancer.