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

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.

Oncotarget. 2016 Jul 12 [Epub ahead of print]

Nakho Chang, Hye Won Lee, Joung Eun Lim, Da Eun Jeong, Hye Jin Song, Sudong Kim, Do-Hyun Nam, Hyun Hwan Sung, Byong Chang Jeong, Seong Il Seo, Seong Soo Jeon, Hyun Moo Lee, Han-Yong Choi, Hwang Gyun Jeon

Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul 06351, Korea., Institute for Refractory Cancer Research, Samsung Medical Center, Seoul 06351, Korea., Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea., Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul 06351, Korea., Department of Anatomy and Cell Biology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea., Institute for Refractory Cancer Research, Samsung Medical Center, Seoul 06351, Korea., Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul 06351, Korea., Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea., Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea., Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea., Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea., Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea., Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea., Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea.

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