Selective impact of CDK4/6 suppression on patient-derived models of pancreatic cancer

Agnieszka K. Witkiewicz, Nicholas A. Borja, Jorge Franco, Jonathan R. Brody, Charles J. Yeo, John Mansour, Michael A. Choti, Peter McCue, Erik S. Knudsen

Research output: Contribution to journalArticle

32 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)15788-15801
Number of pages14
JournalOncotarget
Volume6
Issue number18
DOIs
StatePublished - 2015

Keywords

  • CDk4/6
  • PD-0332991
  • Pancreatic cancer
  • Patient-derived xenograft
  • Tumor explant

ASJC Scopus subject areas

  • Oncology

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    Witkiewicz, A. K., Borja, N. A., Franco, J., Brody, J. R., Yeo, C. J., Mansour, J., Choti, M. A., McCue, P., & Knudsen, E. S. (2015). Selective impact of CDK4/6 suppression on patient-derived models of pancreatic cancer. Oncotarget, 6(18), 15788-15801. https://doi.org/10.18632/oncotarget.3819