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. 2023 Jul;22(13):1563-1582.
doi: 10.1080/15384101.2023.2217003. Epub 2023 Jun 2.

CDK4/6 inhibition confers protection of normal gut epithelia against gemcitabine and the active metabolite of irinotecan

Joshua Blume  1 , Luisa Claus  1 , Tamara Isermann  1 , Antje Dickmanns  1 , Lena-Christin Conradi  2 , Ramona Schulz-Heddergott  1 , Matthias Dobbelstein  1
Affiliations

CDK4/6 inhibition confers protection of normal gut epithelia against gemcitabine and the active metabolite of irinotecan

Joshua Blume et al. Cell Cycle. 2023 Jul.

Abstract

Cancer chemotherapy relies on a high ratio of toxicity toward cancer cells vs. nonmalignant cells, making it desirable to protect normal cells. Among the nonmalignant cells, epithelia of the gut belong to the most vulnerable ones toward chemotherapeutics. Here, we use a murine intestinal organoid model to assess a strategy for protecting such epithelia against chemotherapy. Cell cycle progression was first stalled by palbociclib, a clinically established cyclin-dependent kinase 4/6 (CDK4/6) inhibitor. Washout of the drug allowed subsequent outgrowth of gut organoids. This transient cell cycle arrest conferred near-complete protection of the cells toward the nucleoside analogue gemcitabine. Moreover, pre-treatment with palbociclib protected the organoids against SN-38, the topoisomerase I-inhibiting metabolite of irinotecan, which is otherwise known for its severe gastrointestinal toxicities. In contrast, RB1-mutated cancer cells were not protected against gemcitabine or SN-38 when pre-treated with palbociclib. Taken together, these results outline a strategy for protecting nonmalignant cells against the toxicities of chemotherapeutics commonly used to treat advanced colorectal and pancreatic cancer. We propose that this strategy is particularly promising to protect the gut when treating RB1-deficient tumors that fail to arrest the cell cycle in response to CDK4/6 inhibitors. [Figure: see text].

Keywords: CDK4/6; cyclotherapy; gemcitabine; intestinal organoids; irinotecan; palbociclib.

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Conflict of interest statement

No potential conflict of interest was reported by the authors.

Figures

Figure 1.
Figure 1.
Intestinal organoids grow despite transient CDK4/6 inhibition.
Figure 2.
Figure 2.
Palbociclib inhibits the cell cycle in intestinal organoids.
Figure 3.
Figure 3.
Intestinal organoids are protected against gemcitabine by CDK4/6 inhibition.
Figure 4.
Figure 4.
RB1-mutant cancer cells are not protected against gemcitabine by palbociclib.
Figure 5.
Figure 5.
Palbociclib diminishes the cytotoxicity of SN-38, the active metabolite of irinotecan, against intestinal organoids.
Figure 6.
Figure 6.
Palbociclib does not protect RB1-mutant cancer cells against SN-38.
None
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Grants and funding

J. B. thanks the UMG Promotionskolleg, supported by the Else-Kröner-Fresenius-Foundation and the Jacob-Henle-Programm, and the Studienstiftung des Deutschen Volkes for their support .R. S.-H. is supported by the Deutsche Forschungsgemeinschaft (DFG) (SCHUH-3160/3-1). M. D. is supported by the Deutsche Forschungsgemeinschaft, the Deutsche Krebshilfe and the Wilhelm-Sanders-Stiftung.

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