title: Genomic characterization of patient-derived xenograft models established from fine needle aspirate biopsies of a primary pancreatic ductal adenocarcinoma and from patient-matched metastatic sites.
abstract: N-of-1 trials target actionable mutations, yet such approaches do not test genomically-informed therapies in patient tumor models prior to patient treatment. To address this, we developed patient-derived xenograft (PDX) models from fine needle aspiration (FNA) biopsies (FNA-PDX) obtained from primary pancreatic ductal adenocarcinoma (PDAC) at the time of diagnosis. Here, we characterize PDX models established from one primary and two metastatic sites of one patient. We identified an activating KRAS G12R mutation among other mutations in these models. In explant cells derived from these PDX tumor models with a KRAS G12R mutation, treatment with inhibitors of CDKs (including CDK9) reduced phosphorylation of a marker of CDK9 activity (phospho-RNAPII CTD Ser2/5) and reduced viability/growth of explant cells derived from PDAC PDX models. Similarly, a CDK inhibitor reduced phospho-RNAPII CTD Ser2/5, increased apoptosis, and inhibited tumor growth in FNA-PDX and patient-matched metastatic-PDX models. In summary, PDX models can be constructed from FNA biopsies of PDAC which in turn can enable genomic characterization and identification of potential therapies.
authors.affiliation: Department of Pharmacology and Toxicology, Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Allaway
authors.affiliation: Department of Surgery, Division of Surgical Oncology, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA.
authors.forename: Dawn A
authors.initials: DA
authors.lastname: Fischer
authors.affiliation: Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA.
authors.forename: Francine B
authors.initials: FB
authors.lastname: de Abreu
authors.affiliation: Department of Medicine, Section of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA.
authors.forename: Timothy B
authors.initials: TB
authors.lastname: Gardner
authors.affiliation: Department of Medicine, Section of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA.
authors.forename: Stuart R
authors.initials: SR
authors.lastname: Gordon
authors.affiliation: Department of Surgery, Division of Surgical Oncology, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA.|Dartmouth-Hitchcock Norris Cotton Cancer Center, Lebanon, NH 03756, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Barth
authors.affiliation: Department of Surgery, Division of Surgical Oncology, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA.|Dartmouth-Hitchcock Norris Cotton Cancer Center, Lebanon, NH 03756, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Colacchio
authors.affiliation: Department of Pharmacology and Toxicology, Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USA.|Current location: Department of Pathology, University of California, San Francisco, CA 94143, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Wood
authors.affiliation: Department of Genetics, Geisel School of Medicine, Dartmouth College, Hanover, NH 03756, USA.
authors.forename: Balint Z
authors.initials: BZ
authors.lastname: Kacsoh
authors.affiliation: Department of Pharmacology and Toxicology, Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USA.
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Bouley
authors.affiliation: Department of Genetics, Geisel School of Medicine, Dartmouth College, Hanover, NH 03756, USA.
authors.forename: Jingxuan
authors.initials: J
authors.lastname: Cui
authors.affiliation: Department of Pharmacology and Toxicology, Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USA.|Department of Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA.
authors.forename: Joanna
authors.initials: J
authors.lastname: Hamilton
authors.affiliation: Department of Pharmacology and Toxicology, Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USA.
authors.forename: Jungbin A
authors.initials: JA
authors.lastname: Choi
authors.affiliation: Department of Pharmacology and Toxicology, Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USA.
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Lange
authors.affiliation: Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Peterson
authors.affiliation: Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA.
authors.forename: Vijayalakshmi
authors.initials: V
authors.lastname: Padmanabhan
authors.affiliation: Department of Pharmacology and Toxicology, Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USA.|Dartmouth-Hitchcock Norris Cotton Cancer Center, Lebanon, NH 03756, USA.|Department of Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA.
authors.forename: Craig R
authors.initials: CR
authors.lastname: Tomlinson
authors.affiliation: Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA.|Dartmouth-Hitchcock Norris Cotton Cancer Center, Lebanon, NH 03756, USA.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Tsongalis
authors.affiliation: Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA.
authors.forename: Arief A
authors.initials: AA
authors.lastname: Suriawinata
authors.affiliation: Dartmouth-Hitchcock Norris Cotton Cancer Center, Lebanon, NH 03756, USA.|Department of Genetics, Geisel School of Medicine, Dartmouth College, Hanover, NH 03756, USA.|Institute for Quantitative Biomedical Sciences, Dartmouth College, Hanover, NH 03755, USA.
authors.forename: Casey S
authors.initials: CS
authors.lastname: Greene
authors.affiliation: Department of Pharmacology and Toxicology, Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USA.|Dartmouth-Hitchcock Norris Cotton Cancer Center, Lebanon, NH 03756, USA.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Sanchez
authors.affiliation: Department of Surgery, Division of Surgical Oncology, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA.|Dartmouth-Hitchcock Norris Cotton Cancer Center, Lebanon, NH 03756, USA.
authors.forename: Kerrington D
authors.initials: KD
authors.lastname: Smith
mesh_terms: D000818:Animals; D044963:Biopsy, Fine-Needle; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D057285:Precision Medicine / Q000379:methods*; D000075082:Proof of Concept Study; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
keywords: CDK9; KRAS; fine needle aspirate biopsy; pancreatic ductal adenocarcinoma; patient-derived xenograft