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Selective impact of CDK4/6 suppression on patient-derived models of pancreatic cancer
Agnieszka K Witkiewicz1,2, Nicholas A Borja3, Jorge Franco1
1Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA.
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.
Insights
Pancreatic ductal adenocarcinoma (PDA) is often resistant to therapy. However, CDK4/6 inhibition effectively suppresses PDA proliferation in primary models, suggesting potential therapeutic strategies.
Area of Science:
- Oncology
- Cancer Biology
- Molecular Therapeutics
Background:
- Pancreatic ductal adenocarcinoma (PDA) presents a poor prognosis and resistance to conventional therapies.
- Genetic alterations like KRAS mutations and p16ink4a loss are common in PDA.
- CDK4/6 inhibitors show limited efficacy in established PDA cell models and xenografts.
Purpose of the Study:
- To investigate the efficacy of CDK4/6 inhibition in primary pancreatic ductal adenocarcinoma models.
- To identify biomarkers predicting response or resistance to CDK4/6 inhibition in PDA.
- To compare therapeutic responses in primary explants and patient-derived xenografts (PDXs) versus established cell lines.
Main Methods:
- Development of primary pancreatic tumor explants to preserve the tumor microenvironment.
- Treatment of explants and PDXs with the CDK4/6 inhibitor PD-0332991.
- Analysis of proliferation and identification of resistance mechanisms, including RB tumor suppressor loss.
Main Results:
- CDK4/6 inhibition potently suppressed proliferation in 14 out of 15 primary PDA explants.
- Loss of the RB tumor suppressor was identified as a resistance mechanism in one explant.
- Patient-derived xenografts (PDXs) demonstrated high sensitivity to CDK4/6 inhibition, with complete proliferation suppression.
Conclusions:
- Primary pancreatic ductal adenocarcinoma is sensitive to CDK4/6 inhibition.
- RB loss is a biomarker for intrinsic resistance to CDK4/6 inhibitors in PDA.
- Established cell line models may not accurately reflect PDA's therapeutic sensitivity to CDK4/6 inhibition.
