CTA095, a Novel Etk and Src Dual Inhibitor, Induces Apoptosis in Prostate Cancer Cells and Overcomes Resistance to Src Inhibitors

Wenchang Guo,Ruiwu Liu,Caihong Feng,Randen Patterson,Gaurav Bhardwaj,Yuanpei Li,Eduardo Sanchez,Christopher P Evans,Chun Changou,Wenzhe Huang,Ai-Hong Ma,Kit S Lam,Yan Wang,Yan Luo,Hsing-Jien Kung,Anisha Mazloom,Joy C Yang,Qiming Jane Wang

doi:10.1371/journal.pone.0070910

Abstract

Etk is a non-receptor tyrosine kinase, which provides a strong survival signal in human prostate cancer cells. Src, another tyrosine kinase that cross-activates with Etk, has been shown to play an important role in prostate cancer metastasis. Herein, we discovered a new class of Etk inhibitors. Within those inhibitors, CTA095 was identified as a potent Etk and Src dual inhibitor. CTA095 was found to induce autophagy as well as apoptosis in human prostate cancer cells. In addition, CTA095 inhibited HUVEC cell tube formation and “wound healing” of human prostate cancer cells, implying its role in inhibition of angiogenesis and metastasis of human prostate cancer. More interestingly, CTA095 could overcome Src inhibitor resistance in prostate cancer cells. It induces apoptosis in Src inhibitor resistant prostate cancer cells, likely through a mechanism of down regulation of Myc and BCL2. This finding indicates that simultaneously targeting Etk and Src could be a promising approach to overcome drug resistance in prostate cancer.

Highlights

Prostate cancer is the most frequently diagnosed cancer and the second leading cause of cancer deaths of men in the U.S [1]
Recent reports indicate that Etk plays an important role in the self-renewal and tumorigenic potential of glioblastoma stem cells through Stat3 activation [12]
This study revealed that CTA095 was a potent inhibitor for Etk, with an IC50 of approximately 60 nM (Figure 2A)

Summary

Introduction

Prostate cancer is the most frequently diagnosed cancer and the second leading cause of cancer deaths of men in the U.S [1]. While early phase prostate cancer (CaP) can effectively be controlled by hormone therapy, metastatic CaP remains incurable. Tyrosine kinase inhibitors (TKIs) are among the most promising targeted therapies; yet their potential as prostate cancer therapeutics have not been fully realized and, to date, the outcomes of clinical trials using TKIs as single agents have generally been modest, probably due to redundancy in receptor binding and signaling to intracellular mediators [2]. Etk is a non-receptor tyrosine kinase, which is over-expressed in human prostate cancer specimens and provides strong survival functions in prostate cancer cells [3,4]. Etk mediates critical activation of STAT3 in CaP suggesting that functional disruption of Etk may attenuate multiple key signals involved in CaP growth and survival [5]. There is no efficacious inhibitor of this kinase

Methods

Results

Conclusion