Abstract 2960: A novel mouse model of pancreatic cancer reveals new insights into cell cycle deregulation
| Autor: | Elizabeth A. McMillan, Koleen Eisele, Christina Adams, John Chionis, Timothy Affolter, Nichol Miller, Monica Ramstetter, Christopher P. Dillon, Jonathan Almaden, Lynn Wang, Tim S. Wang, Stephen Dann, Todd VanArsdale, Smitha Pillai |
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| Rok vydání: | 2021 |
| Předmět: | |
| Zdroj: | Cancer Research. 81:2960-2960 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | Overcoming checkpoints to cell cycle control is the basis for tumorigenesis and malignant growth. Therefore, models that recapitulate clinically relevant cell cycle deregulation enhance our understanding of defined tumors subsets. Specifically, pancreatic ductal adenocarcinomas (PDAs) frequently delete the 9p21 locus which contains the cyclin dependent kinase (CDK) inhibitors CDKN2A (p16, p14) and CDKN2B (p15), as well as methylthioadenosine phosphorylase (MTAP), a metabolic gene required for methionine salvage from methylthioadenosine. No model currently exists that accurately represents loss of the entire locus in a relevant disease context. Moreover, the contribution of MTAP to tumor progression remains largely unknown. Therefore, we have developed a novel genetically engineered mouse model (GEMM) of PDA which combines loss of the orthologous murine 9p21 region (4qC4) with activated KRAS [Pdx-Cre; LSL-KrasG12D; 9p21L/L (K9C)], which results in rapid adenocarcinoma formation and subsequent mortality in mice homozygous for 9p21 deletion. Single-cell RNA sequencing revealed a remarkable level of inter- and intra-tumoral heterogeneity, including a significant immune and stromal component that contribute to tumor growth and progression. Additionally, K9C derived cell lines are responsive to Pfizer's first-in class CDK2/4/6 selective inhibitor while displaying de novo resistance to CDK4/6 inhibitor Palbociclib. Allograft and single-cell RNA sequencing experiments corroborated these findings and implicate Myc in contributing to CDK2/4/6i sensitivity. Furthermore, phenotypic-based screens revealed synthetic-lethal hits with 9p21 loss, indicating ample opportunities for combination strategies in this select patient population. Thus, we show that the K9C model recapitulates salient aspects of PDA and is amenable to novel therapeutic intervention strategies that may aid in improving the outcomes of patients with this precise genetic background. *All procedures performed on animals were in accordance with regulations and established guidelines and were reviewed and approved by an Institutional Animal Care and use committee Citation Format: Christina Adams, Lynn Wang, Tim S. Wang, Nichol Miller, Elizabeth McMillan, Monica Ramstetter, John Chionis, Koleen Eisele, Jonathan Almaden, Timothy Affolter, Smitha Pillai, Todd VanArsdale, Chris Dillon, Stephen G. Dann. A novel mouse model of pancreatic cancer reveals new insights into cell cycle deregulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2960. |
| Databáze: | OpenAIRE |
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