Establishment and antitumor effects of dasatinib and PKI-587 in BD-138T, a patient-derived muscle invasive bladder cancer preclinical platform with concomitant EGFR amplification and PTEN deletion
Metrics: PDF 1905 views | HTML 2274 views | ?
Nakho Chang1,2,3,*, Hye Won Lee3,4,*, Joung Eun Lim5, Da Eun Jeong1, Hye Jin Song6, Sudong Kim3,7, Do-Hyun Nam1,2,3, Hyun Hwan Sung5, Byong Chang Jeong5, Seong Il Seo5, Seong Soo Jeon5, Hyun Moo Lee5, Han-Yong Choi5, Hwang Gyun Jeon5
1Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul 06351, Korea
2Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
3Institute for Refractory Cancer Research, Samsung Medical Center, Seoul 06351, Korea
4Institute for Future Medicine, Samsung Medical Center, Seoul 06351, Korea
5Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
6Department of Anatomy and Cell Biology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
7Samsung Advanced Institute of Technology, Samsung Electronics Co., Ltd., Seoul 06351, Korea
*These authors contributed equally to this work
Hwang Gyun Jeon, email: [email protected]
Keywords: muscle invasive bladder cancer, PTEN, EGFR, drug screening, patient-derived xenograft
Received: May 20, 2016 Accepted: June 29, 2016 Published: July 12, 2016
Muscle-invasive bladder cancer (MIBC) consists of a heterogeneous group of tumors with a high rate of metastasis and mortality. To facilitate the in-depth investigation and validation of tailored strategies for MIBC treatment, we have developed an integrated approach using advanced high-throughput drug screening and a clinically relevant patient-derived preclinical platform. We isolated patient-derived tumor cells (PDCs) from a rare MIBC case (BD-138T) that harbors concomitant epidermal growth factor receptor (EGFR) amplification and phosphatase and tensin homolog (PTEN) deletion. High-throughput in vitro drug screening demonstrated that dasatinib, a SRC inhibitor, and PKI-587, a dual PI3K/mTOR inhibitor, exhibited targeted anti-proliferative and pro-apoptotic effects against BD-138T PDCs. Using established patient-derived xenograft models that successfully retain the genomic and molecular characteristics of the parental tumor, we confirmed that these anti-tumor responses occurred through the inhibition of SRC and PI3K/AKT/mTOR signaling pathways. Taken together, these experimental results demonstrate that dasatinib and PKI-587 might serve as promising anticancer drug candidates for treating MIBC with combined EGFR gene amplification and PTEN deletion.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.