Salvador-Barbero, BeatrizÁlvarez Fernández, MónicaZapatero-Solana, ElisabetEl Bakkali, AichaMenéndez, María del CaminoLópez Casas, Pedro PabloDi Domenico, TomasXie, TaoVanArsdale, ToddShields, David J.Hidalgo, ManuelMalumbres, Marcos2024-12-192024-12-192020Salvador-Barbero, B., Álvarez-Fernández, M., Zapatero-Solana, E., et al. (2020). CDK4/6 Inhibitors Impair Recovery from Cytotoxic Chemotherapy in Pancreatic Adenocarcinoma. Cancer Cell, 16;37(3):340-3531535-6108https://hdl.handle.net/10641/5547Inhibition 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.engAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/journal articleembargoed access10.1016/j.ccell.2020.01.007