Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a therapy recalcitrant disease characterized by the aberrations in multiple genes that drive pathogenesis and limit therapeutic response. While CDK4/6 represents a downstream target of both KRAS mutation and loss of the CDKN2A tumor suppressor in PDAC, clinical and preclinical studies indicate that pharmacological CDK4/6 inhibitors are only modestly effective. Since chemotherapy represents the established backbone of PDAC treatment we evaluated the interaction of CDK4/6 inhibitors with gemcitabine and taxanes that are employed in the treatment of PDAC. Herein, we demonstrate that the difference in mechanisms of actions of chemotherapeutic agents elicit distinct effects on the cellular response to CDK4/6 inhibition. Gemcitabine largely ablates the function of CDK4/6 inhibition in S-phase arrested cells when administered contemporaneously; although, when cells recover from S-phase block they exhibit sensitivity to CDK4/6 inhibition. In contrast, pharmacological inhibition of CDK4/6 yields a cooperative cytostatic effect in combination with docetaxel and prevents adaptation and cell cycle re-entry, which is a common basis for resistance to such agents. Importantly, using organoid and PDX models we could confirm the cooperative effects between chemotherapy and CDK4/6 inhibition in vivo. These data indicate that the combination of cytotoxic and cytostatic agents could represent an important modality in those tumor types that are relatively resistant to CDK4/6 inhibitors.
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Acknowledgements
The author thanks all members of the laboratory group and colleagues in the discussion and preparation of the manuscript. The research was supported by a grant to AKW and ESK from National Cancer Institute (NCI).
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Study concept and design: VK, ESK, and AKW. Acquisition of data: VK, AR, and RN. Analysis and interpretation of data: VK, ESK, and AKW. Study supervision: ESK and AKW
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ESK and AKW have received research funding from Eli Lilly, Novartis, and Pfizer over the last 5 years. There is no current research support from these entities and the study was written in the absence of input from any pharmaceutical company. The remaining authors declare that they have no conflict of interest.
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Kumarasamy, V., Ruiz, A., Nambiar, R. et al. Chemotherapy impacts on the cellular response to CDK4/6 inhibition: distinct mechanisms of interaction and efficacy in models of pancreatic cancer. Oncogene 39, 1831–1845 (2020). https://doi.org/10.1038/s41388-019-1102-1
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DOI: https://doi.org/10.1038/s41388-019-1102-1
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