Chronic cisplatin treatment promotes enhanced damage repair and tumor progression in a mouse model of lung cancer.
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.
Oliver
Trudy G
TG
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, 02139, USA.
Mercer
Kim L
KL
Sayles
Leanne C
LC
Burke
James R
JR
Mendus
Diana
D
Lovejoy
Katherine S
KS
Cheng
Mei-Hsin
MH
Subramanian
Aravind
A
Mu
David
D
Powers
Scott
S
Crowley
Denise
D
Bronson
Roderick T
RT
Whittaker
Charles A
CA
Bhutkar
Arjun
A
Lippard
Stephen J
SJ
Golub
Todd
T
Thomale
Juergen
J
Jacks
Tyler
T
Sweet-Cordero
E Alejandro
EA
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology* / Q000627:therapeutic use*; D004260:DNA Repair / Q000187:drug effects*; D053418:Death Domain Receptor Signaling Adaptor Proteins; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D020869:Gene Expression Profiling; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis
D000970:Antineoplastic Agents; D002352:Carrier Proteins; D053418:Death Domain Receptor Signaling Adaptor Proteins; C414729:Pidd1 protein, mouse; D002945:Cisplatin
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