In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 2004-2004
Kurzfassung:
Metastasis is the #1 cause of death for cancer patients. It is now well accepted that misregulation of developmental signaling pathways in tumor cells can contribute to the metastatic process. The SIX1/EYA transcriptional complex acts as a master regulatory complex that is involved in the development of numerous organs. This complex has been shown to promote metastasis through activation of TGF-β signaling and consequent induction of epithelial-mesenchymal transition (EMT) in breast cancer. More recently, Six1 has been shown to enhance metastasis in a non-cell autonomous manner, through activation of GLI-signaling in neighboring tumors cells, resulting in increased aggressiveness of cells not directly expressing the transcription factor. The fact that Six1 can regulate metastasis both cell and non-cell autonomously suggests that inhibiting its function would be an effective anti-metastatic approach. Herein, we describe the use of an alpha screen, and the subsequent discovery of a class of small molecule compounds, that disrupt the Six1/Eya2 interaction. We show that our lead compound from the class not only disrupts the SIX1/EYA2 interaction, but also decreases nuclear EYA2 levels, inhibits TGF-β signaling, and reverses EMT. Moreover, our lead compound confers cytostatic effects on tumor cells in a SIX1-dependent manner. To determine whether this novel Six1/Eya2 inhibitor reverses Six1-mediated transcription, we performed RNA-sequencing in the presence and absence of the compound, and found a substantial overlap between targets induced by SIX1 and targets inhibited by the Six1/Eya2 inhibitor. Targets altered by our novel inhibitor are highly enriched in critical developmental process mediated by SIX1. In addition, the Six1/Eya2 inhibitor partially reverses major pathways altered by SIX1 in cancer, including p53 and Hedgehog signaling, as well as pathways associated with cancer stem cells, invasiveness, and EMT. Most critically, our novel Six1/Eya2 inhibitor is well tolerated when delivered IP or IV to mice, and preliminary in vivo experiments demonstrate that the compound can dramatically suppress breast cancer associated metastasis, without significantly altering primary tumor growth. In summary, our study identified a novel class of compounds that target the SIX1/EYA2 complex, and demonstrate for the first time that pharmacological inhibition of this complex is sufficient to suppress breast cancer metastasis. Citation Format: Hengbo Zhou, Melanie Blevins, Lingdi Zhang, Deguang Kong, Michael Oliphant, Daniel L. Gustafson, Samarjit Patnaik, Juan Marugan, Rui Zhao, Heide L. Ford. Identification of a novel small molecule inhibitor of the Six1/Eya2 complex and in vivo metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2004.
Materialart:
Online-Ressource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2019-2004
Sprache:
Englisch
Verlag:
American Association for Cancer Research (AACR)
Publikationsdatum:
2019
ZDB Id:
2036785-5
ZDB Id:
1432-1
ZDB Id:
410466-3
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