Palbociclib Effectively Halts Proliferation but Fails to Induce Senescence in Patient-Derived Glioma Stem Cells

OLIVIA MORRIS-HANON; MARIELA CLAUDIA MARAZITA; LEONARDO ROMORINI; LUCIANA ISAJA; DAMIáN D. FERNANDEZ ESPINOSA; GUSTAVO SEVLEVER; MARIA ELIDAD SCASSA; GUILLERMO A. VIDELA RICHARDSON

MOLECULAR NEUROBIOLOGY

HUMANA PRESS INC

Año: 2019

0893-7648

Glioblastoma multiforme is the most aggressive primary brain tumor. Current knowledge suggests that the growth and recurrence of these tumors are due in part to the therapy-resistant glioma stem cell subpopulation, which possesses the ability for selfrenewal and proliferation, driving tumor progression. In many cancers, the p16INK4a-CDK4/6-pRb pathway is disrupted in favor of cell cycle progression. In particular, the frequent deregulation of CDK4/6 in cancer positions these kinases as promisingtargets. Palbociclib, a potent and selective CDK4/6 inhibitor, has been approved by the FDA as a first-line treatment of advancedbreast cancer and there is currently interest in evaluating its effect on other cancer types. Palbociclib has been reported to be efficient, not only at halting proliferation, but also at inducing senescence in different tumor types. In this study, we evaluated theeffect of this inhibitor on four patient-derived glioma stem cell-enriched cell lines. We found that Palbociclib rapidly andeffectively inhibits proliferation without affecting cell viability. We also established that in these cell lines CDK6 is the keyinterphase CDK for controlling cell cycle progression. Prolonged exposure to Palbociclib induced a senescent-like phenotypecharacterized by flattened morphology, cell cycle arrest, increased â-galactosidase activity and induction of other senescentassociated markers. However, we found that after Palbociclib removal cell lines resumed normal proliferation, which implies they conserved their replicative potential. As a whole, our results indicate that in patient-derived glioma stem cell-enriched cell lines,Palbociclib induces a senescent-like quiescence rather than true senescence.