title: Selective impact of CDK4/6 suppression on patient-derived models of pancreatic cancer.
abstract: Pancreatic ductal adenocarcinoma (PDA) harbors an exceedingly poor prognosis, and is generally considered a therapy-recalcitrant disease due to poor response to conventional chemotherapy coupled with non-actionable genetic drivers (e.g. KRAS mutations). However, PDA frequently loses p16ink4a, thereby leading to deregulation of CDK4/6. Surprisingly, in established cell models and xenografts, CDK4/6 inhibition has a modest effect on proliferation and resistance develops rapidly. To determine if such weak response was an intrinsic feature of PDA, we developed primary tumor explants that maintain the tumor environment and recapitulate feuture of primary PDA. The CDK4/6 inhibitor PD-0332991 was highly efficient at suppressing proliferation in 14 of the 15 explants. In the single resistant explant, we identified the rare loss of the RB tumor suppressor as the basis for resistance. Patient-derived xenografts (PDXs) were developed in parallel, and unlike the xenografts emerging from established cell lines, the PDXs maintained the histoarchitecture of the primary tumor. These PDXs were highly sensitive to CDK4/6 inhibition, yielding a complete suppression of PDA proliferation. Together, these data indicate that primary PDA is sensitive to CDK4/6 inhibition, that specific biomarkers can delineate intrinsic resistance, and that established cell line models may not represent an adequate means for evaluating therapeutic sensitivities.
authors.affiliation: Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA.|Simmons Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Agnieszka K
authors.initials: AK
authors.lastname: Witkiewicz
authors.affiliation: Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Borja
authors.affiliation: Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Jorge
authors.initials: J
authors.lastname: Franco
authors.affiliation: Department of Pathology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Brody
authors.affiliation: Department of Surgery, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Yeo
authors.affiliation: Simmons Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA.|Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: John
authors.initials: J
authors.lastname: Mansour
authors.affiliation: Simmons Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA.|Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Choti
authors.affiliation: Department of Pathology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: McCue
authors.affiliation: Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA.|Simmons Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Erik S
authors.initials: ES
authors.lastname: Knudsen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010190:Pancreatic Neoplasms; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; C500026:palbociclib
keywords: CDK4/6; PD-0332991; pancreatic cancer; patient-derived xenograft; tumor explant