A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy


  • C.A. Schmitt
  • J.S. Fridman
  • M. Yang
  • S. Lee
  • E. Baranov
  • R.M. Hoffman
  • S.W. Lowe


  • Cell


  • Cell 109 (3): 335-346


  • p53 and INK4a/ARF mutations promote tumorigenesis and drug resistance, in part, by disabling apoptosis. We show that primary murine lymphomas also respond to chemotherapy by engaging a senescence program controlled by p53 and p16INK4a. Hence, tumors with p53 or INK4a/ARF mutations—but not those lacking ARF alone—respond poorly to cyclophosphamide therapy in vivo. Moreover, tumors harboring a Bcl2-mediated apoptotic block undergo a drug-induced cytostasis involving the accumulation of p53, p16INK4a, and senescence markers, and typically acquire p53 or INK4a mutations upon progression to a terminal stage. Finally, mice bearing tumors capable of drug-induced senescence have a much better prognosis following chemotherapy than those harboring tumors with senescence defects. Therefore, cellular senescence contributes to treatment outcome in vivo.