Palbociclib in daily clinical use: Real world experience of the breast center at the University Hospital Munich

Hester, Allison; Köenig, Alexander; Dobler, Franziska; Degenhardt, Tom; Heidegger-Steger, H; Kurt, A; Kahlert, Steffen; Mahner, S; Harbeck, Nadia; Wuerstlein, Rachel

doi:10.1093/annonc/mdz100.031

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“…CDK4 and CDK6 dual inhibitors, which block the kinase activity by preventing ATP from binding to the kinase pocket, have successfully entered the clinics. Palbociclib (Ibrance ® by Pfizer), ribociclib (Kisqali ® by Novartis) and abemaciclib (Verzenios ® by Lily) have been approved for HER2-negative, locally advanced or metastatic breast cancer 23 and are currently undergoing clinical trials to test their efficacy in solid tumors and leukemia. 24 Recently, CDK6 expression was identified to be a conserved and direct target of diverse NUP98-fusions driving aggressive forms of acute myeloid leukemia, which were demonstrated to be hypersensitive to CDK4/6 inhibition.…”

Section: Introductionmentioning

confidence: 99%

Inducible deletion of CDK4 and CDK6 – deciphering CDK4/6 inhibitor effects in the hematopoietic system

et al. 2020

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Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors are considered a breakthrough in cancer therapy. Currently approved for breast cancer treatment, CDK4/6 inhibitors are extensively tested in other cancer subtypes. Frequently observed side effects include hematological abnormalities such as reduced numbers of neutrophils, erythroid cells and platelets that are associated with anemia, bleeding and a higher risk of infections. In order to understand whether the adverse effects within the hematopoietic system are related to CDK4 or CDK6 we generated transgenic mice that lack either CDK4 or CDK6 in adult hematopoiesis. Anemia and perturbed erythroid differentiation are associated with the absence of CDK6 but did not manifest in CDK4- deficient mice. Total CDK6 knockout mice accumulate the most dormant fraction of hematopoietic stem cells due to an impaired exit of the quiescent state. We recapitulated this finding by deleting CDK6 in adult hematopoiesis. In addition, unlike total CDK6 knockout, all stem cell fractions were affected and increased in numbers. The deletion of CDK6 was also accompanied by neutropenia which is frequently seen in patients receiving CDK4/6 inhibitors. This was not the case in the absence of CDK4; CDK4 deficiency resulted in elevated numbers of myeloid progenitors without translating into numeric changes of differentiated myeloid cells. By using Cdk4fl/fl and Cdk6fl/fl mice we assign side effects of CDK4/6 inhibitors predominantly to the absence of CDK6. These mice represent a novel and powerful tool that will enable to study the distinct functions of CDK4 and CDK6 in a tissue-dependent manner.

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Section: Introductionmentioning

confidence: 99%