Oncotarget

Priority Research Papers:

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 and Erik S. Knudsen

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Oncotarget. 2015; 6:15788-15801. https://doi.org/10.18632/oncotarget.3819

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Abstract

Agnieszka K. Witkiewicz1,2, Nicholas A. Borja3, Jorge Franco1, Jonathan R. Brody4, Charles J. Yeo5, John Mansour2,3, Michael A. Choti2,3, Peter McCue4 and Erik S. Knudsen1,2

1 Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA

2 Simmons Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA

3 Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA

4 Department of Pathology, Thomas Jefferson University, Philadelphia, PA, USA

5 Department of Surgery, Thomas Jefferson University, Philadelphia, PA, USA

Correspondence to:

Agnieszka K. Witkiewicz, email:

Erik Knudsen, email:

Keywords: CDK4/6, pancreatic cancer, PD-0332991, patient-derived xenograft, tumor explant

Received: February 05, 2015 Accepted: March 01, 2015 Published: April 14, 2015

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.


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