title: Integrated Patient-Derived Models Delineate Individualized Therapeutic Vulnerabilities of Pancreatic Cancer.
abstract: Pancreatic ductal adenocarcinoma (PDAC) harbors the worst prognosis of any common solid tumor, and multiple failed clinical trials indicate therapeutic recalcitrance. Here, we use exome sequencing of patient tumors and find multiple conserved genetic alterations. However, the majority of tumors exhibit no clearly defined therapeutic target. High-throughput drug screens using patient-derived cell lines found rare examples of sensitivity to monotherapy, with most models requiring combination therapy. Using PDX models, we confirmed the effectiveness and selectivity of the identified treatment responses. Out of more than 500 single and combination drug regimens tested, no single treatment was effective for the majority of PDAC tumors, and each case had unique sensitivity profiles that could not be predicted using genetic analyses. These data indicate a shortcoming of reliance on genetic analysis to predict efficacy of currently available agents against PDAC and suggest that sensitivity profiling of patient-derived models could inform personalized therapy design for PDAC.
authors: McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390, USA; Simmons Cancer Center, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390, USA; Department of Pathology, University of Arizona, 1501 N. Campbell Street, Tucson, AZ 85724, USA; University of Arizona Cancer Center, University of Arizona, 1515 N. Campbell Street, Tucson, AZ 85724, USA. Electronic address: awitki@email.arizona.edu.
authors: Agnieszka K
authors: AK
authors: Witkiewicz
authors: McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390, USA.
authors: Uthra
authors: U
authors: Balaji
authors: McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390, USA.
authors: Cody
authors: C
authors: Eslinger
authors: Department of Cell Biology, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390, USA.
authors: Elizabeth
authors: E
authors: McMillan
authors: Department of Surgery, Ochsner Medical Center, 1514 Jefferson Highway, Jefferson, LA 70121, USA.
authors: William
authors: W
authors: Conway
authors: Department of Biochemistry, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390, USA.
authors: Bruce
authors: B
authors: Posner
authors: Department of Systems Biology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors: Gordon B
authors: GB
authors: Mills
authors: David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, 1275 York Street, New York, NY 10065, USA.
authors: Eileen M
authors: EM
authors: O'Reilly
authors: McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390, USA; Simmons Cancer Center, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390, USA; University of Arizona Cancer Center, University of Arizona, 1515 N. Campbell Street, Tucson, AZ 85724, USA; Department of Medicine, University of Arizona, 1515 N. Campbell Street, Tucson, AZ 85724, USA. Electronic address: eknudsen@email.arizona.edu.
authors: Erik S
authors: ES
authors: Knudsen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D021441:Carcinoma, Pancreatic Ductal / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D000069439:Dasatinib / Q000494:pharmacology; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D000068338:Everolimus / Q000494:pharmacology; D059472:Exome; D006801:Humans; D051379:Mice; D008957:Models, Genetic; D015233:Models, Statistical; D010190:Pancreatic Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D057285:Precision Medicine; D011379:Prognosis; D011728:Pyridones / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology; D043823:Taxoids / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D011728:Pyridones; D011744:Pyrimidinones; D043823:Taxoids; D000077143:Docetaxel; C560077:trametinib; D000068338:Everolimus; D000069439:Dasatinib