Small molecules inhibiting the nuclear localization of YAP/TAZ for chemotherapeutics and chemosensitizers against breast cancers

Yusuke Oku; Naoyuki Nishiya; Toshiya Shito; Reiichiro Yamamoto; Yasufumi Yamamoto; Chihiro Oyama; Yoshimasa Uehara

doi:10.1016/j.fob.2015.06.007

Small molecules inhibiting the nuclear localization of YAP/TAZ for chemotherapeutics and chemosensitizers against breast cancers

FEBS Open Bio. 2015 Jun 22:5:542-9. doi: 10.1016/j.fob.2015.06.007. eCollection 2015.

Authors

Yusuke Oku¹, Naoyuki Nishiya¹, Toshiya Shito¹, Reiichiro Yamamoto¹, Yasufumi Yamamoto¹, Chihiro Oyama¹, Yoshimasa Uehara¹

Affiliation

¹ Department of Microbial Chemical Biology and Drug Discovery, Iwate Medical University School of Pharmaceutical Sciences, 2-1-1 Nishitokuta, Yahaba-cho, Shiwa-gun, Iwate 028-3694, Japan.

Abstract

YAP and TAZ oncoproteins confer malignancy and drug resistance to various cancer types. We screened for small molecules that inhibit the nuclear localization of YAP/TAZ. Dasatinib, statins and pazopanib inhibited the nuclear localization and target gene expression of YAP and TAZ. All three drugs induced phosphorylation of YAP and TAZ, and pazopanib induced proteasomal degradation of YAP/TAZ. The sensitivities to these drugs are correlated with dependence on YAP/TAZ in breast cancer cell lines. Combinations of these compounds with each other or with other anti-cancer drugs efficiently reduced cell proliferation of YAP/TAZ-dependent breast cancer cells. These results suggest that these drugs can be therapeutics and chemosensitizers for YAP/TAZ-dependent breast cancers.

Keywords: CTGF, connective tissue growth factor; Combination therapy; Dasatinib; FDA, food and drug administration; GPCR, G-protein coupled receptor; HMG-CoA, hydroxymethylglutaryl-coenzyme A; NF2, neurofibromin 2; Pazopanib; Statins; TAZ; TAZ, transcriptional coactivator with PDZ-binding motif; TEAD, TEA domain family member; YAP; YAP, yes-associated protein.