title: Guidance to rational use of pharmaceuticals in gallbladder sarcomatoid carcinoma using patient-derived cancer cells and whole exome sequencing.
abstract: OBJECTIVE
  Gallbladder sarcomatoid carcinoma is a rare cancer with no clinical standard treatment. With the rapid development of next generation sequencing, it has been able to provide reasonable treatment options for patients based on genetic variations. However, most cancer drugs are not approval for gallbladder sarcomatoid carcinoma indications. The correlation between drug response and a genetic variation needs to be further elucidated.
  
  
  METHODS
  Three patient-derived cells-JXQ-3D-001, JXQ-3D-002, and JXQ-3D-003, were derived from biopsy samples of one gallbladder sarcomatoid carcinoma patient with progression and have been characterized. In order to study the relationship between drug sensitivity and gene alteration, genetic mutations of three patient-derived cells were discovered by whole exome sequencing, and drug screening has been performed based on the gene alterations and related signaling pathways that are associated with drug targets.
  
  
  RESULTS
  It has been found that there are differences in biological characteristics such as morphology, cell proliferation, cell migration and colony formation activity among these three patient-derived cells although they are derived from the same patient. Their sensitivities to the chemotherapy drugs-Fluorouracil, Doxorubicin, and Cisplatin are distinct. Moreover, none of common chemotherapy drugs could inhibit the proliferations of all three patient-derived cells. Comprehensive analysis of their whole exome sequencing demonstrated that tumor-associated genes TP53, AKT2, FGFR3, FGF10, SDHA, and PI3KCA were mutated or amplified. Part of these alterations are actionable. By screening a set of compounds that are associated with the genetic alteration, it has been found that GDC-0941 and PF-04691502 for PI3K-AKT-mTOR pathway inhibitors could dramatically decrease the proliferation of three patient-derived cells. Importantly, expression of phosphorylated AKT and phosphorylated S6 were markedly decreased after treatments with PI3K-AKT-mTOR pathway inhibitors GDC-0941 (0.5 μM) and PF-04691502 (0.1 μM) in all three patient-derived cells. These data suggested that inhibition of the PI3K-AKT-mTOR pathway that was activated by PIK3CA amplification in all three patient-derived cells could reduce the cell proliferation.
  
  
  CONCLUSIONS
  A patient-derived cell model combined with whole exome sequencing is a powerful tool to elucidate relationship between drug sensitivities and genetic alternations. In these gallbladder sarcomatoid carcinoma patient-derived cells, it is found that PIK3CA amplification could be used as a biomarker to indicate PI3K-AKT-mTOR pathway activation. Block of the pathway may benefit the gallbladder sarcomatoid carcinoma patient with this alternation in hypothesis. The real efficacy needs to be confirmed in vivo or in a clinical trial.
authors.affiliation: Department of Biliary I, Third Affiliated Hospital of PLA Second Military Medical University, Shanghai, China.
authors.forename: Feiling
authors.initials: F
authors.lastname: Feng
authors.affiliation: Department of Biliary I, Third Affiliated Hospital of PLA Second Military Medical University, Shanghai, China.
authors.forename: Qingbao
authors.initials: Q
authors.lastname: Cheng
authors.affiliation: Department of Biliary I, Third Affiliated Hospital of PLA Second Military Medical University, Shanghai, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Yang
authors.affiliation: Division of Translational Medicine, 3D Medicines Corporation, Shanghai, China.|Changhai Hospital, The Second Military Medical University, Shanghai, China.
authors.forename: Dadong
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Division of Translational Medicine, 3D Medicines Corporation, Shanghai, China.
authors.forename: Shunlong
authors.initials: S
authors.lastname: Ji
authors.affiliation: Division of Translational Medicine, 3D Medicines Corporation, Shanghai, China.
authors.forename: Qiangzu
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Division of Translational Medicine, 3D Medicines Corporation, Shanghai, China.
authors.forename: Yihui
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Division of Translational Medicine, 3D Medicines Corporation, Shanghai, China.
authors.forename: Fugen
authors.initials: F
authors.lastname: Li
authors.affiliation: Division of Translational Medicine, 3D Medicines Corporation, Shanghai, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Xiong
authors.affiliation: Department of Biliary I, Third Affiliated Hospital of PLA Second Military Medical University, Shanghai, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Biliary I, Third Affiliated Hospital of PLA Second Military Medical University, Shanghai, China.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Jiang
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000235:genetics; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D005706:Gallbladder Neoplasms / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D000073359:Exome Sequencing
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor
keywords: PIK3CA amplification; drug sensitivity; gallbladder sarcomatoid carcinoma (GSC); patient-derived cancer cell (PDC); whole exome sequencing (WES)