Retinoblastoma deficiency increases chemosensitivity in lung cancer.
The retinoblastoma (RB) tumor suppressor is mutated or functionally inactivated in the majority of human malignancies, and p16(INK4a)-cyclin D1-cyclin-dependent kinase 4-RB pathway aberrations are present in nearly all cases of non-small cell lung cancer (NSCLC). Here, the distinct role of RB loss in tumorigenic proliferation and sensitivity to chemotherapeutics was determined in NSCLC cells. Attenuation of RB led to a proliferative advantage in vitro and aggressive tumorigenic growth in xenograft models. Clinically, such aggressive disease is treated with genotoxic and cytotoxic chemotherapeutic agents. In vitro analysis showed that RB deficiency resulted in bypass of the checkpoint response to multiple chemotherapeutic challenges concomitant with an elevated apoptotic response. Correspondingly, RB deficiency in xenograft models led to increased chemosensitivity. However, this response was transient, and a durable response was dependent on prolonged chemotherapeutic administration. Together, these findings show that although RB deficiency enhances sensitivity to chemotherapeutic challenge, efficient and sustainable response is highly dependent on the specific therapeutic regimen, in addition to the molecular environment.
Zagorski
William A
WA
Division of Thoracic Surgery, Department of Surgery, The Vontz Center for Molecular Studies, University of Cincinnati College of Medicine and Department of Surgery, Cincinnati VA Medical Center, Cincinnati, OH 45267-0558, USA.
Knudsen
Erik S
ES
Reed
Michael F
MF
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics*; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D016160:Retinoblastoma Protein / Q000235:genetics*; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays