Therapeutic targeting of Chk1 in NSCLC stem cells during chemotherapy

Ruggero De Maria Marchiano, Simone Maria Navarra, M. Bartucci, S. Svensson, P. Romania, R. Dattilo, M. Patrizii, M. Signore, S. Navarra, F. Lotti, M. Biffoni, E. Pilozzi, E. Duranti, S. Martinelli, C. Rinaldo, A. Zeuner, M. Maugeri-Saccà, A. Eramo

Risultato della ricerca: Contributo in rivistaArticolo in rivista

119 Citazioni (Scopus)

Abstract

Cancer stem cell (SC) chemoresistance may be responsible for the poor clinical outcome of non-small-cell lung cancer (NSCLC) patients. In order to identify the molecular events that contribute to NSCLC chemoresistance, we investigated the DNA damage response in SCs derived from NSCLC patients. We found that after exposure to chemotherapeutic drugs NSCLC-SCs undergo cell cycle arrest, thus allowing DNA damage repair and subsequent cell survival. Activation of the DNA damage checkpoint protein kinase (Chk) 1 was the earliest and most significant event detected in NSCLC-SCs treated with chemotherapy, independently of their p53 status. In contrast, a weak Chk1 activation was found in differentiated NSCLC cells, corresponding to an increased sensitivity to chemotherapeutic drugs as compared with their undifferentiated counterparts. The use of Chk1 inhibitors in combination with chemotherapy dramatically reduced NSCLC-SC survival in vitro by inducing premature cell cycle progression and mitotic catastrophe. Consistently, the co-administration of the Chk1 inhibitor AZD7762 and chemotherapy abrogated tumor growth in vivo, whereas chemotherapy alone was scarcely effective. Such increased efficacy in the combined use of Chk1 inhibitors and chemotherapy was associated with a significant reduction of NSCLC-SCs in mouse xenografts. Taken together, these observations support the clinical evaluation of Chk1 inhibitors in combination with chemotherapy for a more effective treatment of NSCLC. © 2012 Macmillan Publishers Limited. All rights reserved.
Lingua originaleEnglish
pagine (da-a)768-778
Numero di pagine11
RivistaCell Death and Differentiation
Volume19
DOI
Stato di pubblicazionePubblicato - 2012

Keywords

  • Animals
  • Blotting, Western
  • Carcinoma, Non-Small-Cell Lung
  • Cell Biology
  • Cell Cycle
  • Cell Differentiation
  • Cell Proliferation
  • Cell Survival
  • Checkpoint Kinase 1
  • Chk1 inhibitors
  • Cisplatin
  • DNA Damage
  • DNA damage
  • Deoxycytidine
  • Enzyme Inhibitors
  • Female
  • Fluorescent Antibody Technique
  • Humans
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Molecular Biology
  • Neoplastic Stem Cells
  • Protein Kinases
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays
  • chemoresistance
  • lung cancer stem cells
  • mitotic catastrophe

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