title: 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.
abstract: 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.
authors.affiliation: Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul 06351, Korea.|Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea.|Institute for Refractory Cancer Research, Samsung Medical Center, Seoul 06351, Korea.
authors.forename: Nakho
authors.initials: N
authors.lastname: Chang
authors.affiliation: Institute for Refractory Cancer Research, Samsung Medical Center, Seoul 06351, Korea.|Institute for Future Medicine, Samsung Medical Center, Seoul 06351, Korea.
authors.forename: Hye Won
authors.initials: HW
authors.lastname: Lee
authors.affiliation: Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea.
authors.forename: Joung Eun
authors.initials: JE
authors.lastname: Lim
authors.affiliation: Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul 06351, Korea.
authors.forename: Da Eun
authors.initials: DE
authors.lastname: Jeong
authors.affiliation: Department of Anatomy and Cell Biology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea.
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Song
authors.affiliation: Institute for Refractory Cancer Research, Samsung Medical Center, Seoul 06351, Korea.|Samsung Advanced Institute of Technology, Samsung Electronics Co., Ltd., Seoul 06351, Korea.
authors.forename: Sudong
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul 06351, Korea.|Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea.|Institute for Refractory Cancer Research, Samsung Medical Center, Seoul 06351, Korea.
authors.forename: Do-Hyun
authors.initials: DH
authors.lastname: Nam
authors.affiliation: Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea.
authors.forename: Hyun Hwan
authors.initials: HH
authors.lastname: Sung
authors.affiliation: Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea.
authors.forename: Byong Chang
authors.initials: BC
authors.lastname: Jeong
authors.affiliation: Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea.
authors.forename: Seong Il
authors.initials: SI
authors.lastname: Seo
authors.affiliation: Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea.
authors.forename: Seong Soo
authors.initials: SS
authors.lastname: Jeon
authors.affiliation: Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea.
authors.forename: Hyun Moo
authors.initials: HM
authors.lastname: Lee
authors.affiliation: Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea.
authors.forename: Han-Yong
authors.initials: HY
authors.lastname: Choi
authors.affiliation: Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea.
authors.forename: Hwang Gyun
authors.initials: HG
authors.lastname: Jeon
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D000069439:Dasatinib / Q000494:pharmacology* / Q000627:therapeutic use; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D066246:ErbB Receptors / Q000235:genetics*; D005784:Gene Amplification; D017353:Gene Deletion; D006801:Humans; D008297:Male; D008875:Middle Aged; D019042:Muscle Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000556:secondary; D009154:Mutation; D009361:Neoplasm Invasiveness; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D061251:Primary Cell Culture / Q000379:methods; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*
chemical_list: D000970:Antineoplastic Agents; C512478:EGFR protein, human; D066246:ErbB Receptors; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D000069439:Dasatinib
keywords: EGFR; PTEN; drug screening; muscle invasive bladder cancer; patient-derived xenograft