Chronic cisplatin treatment promotes enhanced damage repair and tumor progression in a mouse model of lung cancer
Author(s)Oliver, Trudy; Mercer, Kim L.; Sayles, Leanne C.; Burke, James R.; Mendus, Diana; Lovejoy, Katherine S.; Cheng, Mei-Hsin; Subramanian, Aravind; Mu, David; Powers, Scott; Crowley, Denise G.; Bronson, Roderick T.; Whittaker, Charles A.; Bhutkar, Arjun (AJ); Lippard, Stephen J.; Golub, Todd R.; Thomale, Juergen; Jacks, Tyler E.; Sweet-Cordero, E. Alejandro; ... Show more Show less
MetadataShow full item record
Chemotherapy resistance is a major obstacle in cancer treatment, yet the mechanisms of response to specific therapies have been largely unexplored in vivo. Employing genetic, genomic, and imaging approaches, we examined the dynamics of response to a mainstay chemotherapeutic, cisplatin, in multiple mouse models of human non-small-cell lung cancer (NSCLC). We show that lung tumors initially respond to cisplatin by sensing DNA damage, undergoing cell cycle arrest, and inducing apoptosis—leading to a significant reduction in tumor burden. Importantly, we demonstrate that this response does not depend on the tumor suppressor p53 or its transcriptional target, p21. Prolonged cisplatin treatment promotes the emergence of resistant tumors with enhanced repair capacity that are cross-resistant to platinum analogs, exhibit advanced histopathology, and possess an increased frequency of genomic alterations. Cisplatin-resistant tumors express elevated levels of multiple DNA damage repair and cell cycle arrest-related genes, including p53-inducible protein with a death domain (Pidd). We demonstrate a novel role for PIDD as a regulator of chemotherapy response in human lung tumor cells.
DepartmentMassachusetts Institute of Technology. Department of Biology; Massachusetts Institute of Technology. Department of Chemistry; Koch Institute for Integrative Cancer Research at MIT
Genes and Development
Cold Spring Harbor Laboratory Press in association with The Genetics Society
Oliver, Trudy G. et al. “Chronic Cisplatin Treatment Promotes Enhanced Damage Repair and Tumor Progression in a Mouse Model of Lung Cancer.” Genes & Development 24.8 (2010) : 837 -852.
Author's final manuscript