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. 2020 Mar 16;37(3):340-353.e6.
doi: 10.1016/j.ccell.2020.01.007. Epub 2020 Feb 27.

CDK4/6 Inhibitors Impair Recovery from Cytotoxic Chemotherapy in Pancreatic Adenocarcinoma

Beatriz Salvador-Barbero  1 , Mónica Álvarez-Fernández  2 , Elisabet Zapatero-Solana  2 , Aicha El Bakkali  2 , María Del Camino Menéndez  3 , Pedro P López-Casas  3 , Tomas Di Domenico  4 , Tao Xie  5 , Todd VanArsdale  5 , David J Shields  6 , Manuel Hidalgo  7 , Marcos Malumbres  8
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CDK4/6 Inhibitors Impair Recovery from Cytotoxic Chemotherapy in Pancreatic Adenocarcinoma

Beatriz Salvador-Barbero et al. Cancer Cell. .
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Abstract

Inhibition of the cell-cycle kinases CDK4 and CDK6 is now part of the standard treatment in advanced breast cancer. CDK4/6 inhibitors, however, are not expected to cooperate with DNA-damaging or antimitotic chemotherapies as the former prevent cell-cycle entry, thus interfering with S-phase- or mitosis-targeting agents. Here, we report that sequential administration of CDK4/6 inhibitors after taxanes cooperates to prevent cellular proliferation in pancreatic ductal adenocarcinoma (PDAC) cells, patient-derived xenografts, and genetically engineered mice with Kras G12V and Cdkn2a-null mutations frequently observed in PDAC. This effect correlates with the repressive activity of CDK4/6 inhibitors on homologous recombination proteins required for the recovery from chromosomal damage. CDK4/6 inhibitors also prevent recovery from multiple DNA-damaging agents, suggesting broad applicability for their sequential administration after available chemotherapeutic agents.

Keywords: CDK4/6 inhibitors; cell cycle; chemotherapy; pancreatic adenocarcinoma.

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Conflict of interest statement

Declaration of Interests D.J.S., T.X., and T.V.A. are employees of Pfizer and hold shares in the company. M.H. declares stock and ownership interests (Champions Oncology, Pharmacyte Biotech, BioOncotech, Nelum, Eng T Cells), received honoraria (Pfizer, Novartis, MSD Oncology, Celgene, BiolineRx, Champions Oncology, Roche, SOBI, Agenus, Erytech Pharma, Pharmacyte Biotech), had consulting or advisory roles (Oncomatryx Biopharma, Novartis, Pfizer, Celgene, Merck, Champions Oncology, Pharmacyte Biotech, SOBI, Roche, BiolineRx, Erytech Pharma, Agenus, Bayer, Bristol-Myers Squibb, Nelum, Eng T Cells, InxMed; Bioncotech, Takeda), received research funding (Berg, Oncomatryx Biopharma, Pfizer, Celgene, Bicycle Therapeutics, BiolineRx, Asana Biosciences), and participates in patents, royalties, and other Intellectual Property from Myriad Genetics. M.M. has had advisory or consulting relationships, or research agreements with Pfizer, Eli Lilly, and Novartis. The other authors declare no competing interests.

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