title: Assessing the radiation response of lung cancer with different gene mutations using genetically engineered mice.
abstract: OBJECTIVE
  Non-small cell lung cancers (NSCLC) are a heterogeneous group of carcinomas harboring a variety of different gene mutations. We have utilized two distinct genetically engineered mouse models of human NSCLC (adenocarcinoma) to investigate how genetic factors within tumor parenchymal cells influence the in vivo tumor growth delay after one or two fractions of radiation therapy (RT).
  
  
  METHODS
  Primary lung adenocarcinomas were generated in vivo in mice by intranasal delivery of an adenovirus expressing Cre-recombinase. Lung cancers expressed oncogenic Kras(G12D) and were also deficient in one of two tumor suppressor genes: p53 or Ink4a/ARF. Mice received no radiation treatment or whole lung irradiation in a single fraction (11.6 Gy) or in two 7.3 Gy fractions (14.6 Gy total) separated by 24 h. In each case, the biologically effective dose (BED) equaled 25 Gy10. Response to RT was assessed by micro-CT 2 weeks after treatment. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and immunohistochemical staining were performed to assess the integrity of the p53 pathway, the G1 cell-cycle checkpoint, and apoptosis.
  
  
  RESULTS
  Tumor growth rates prior to RT were similar for the two genetic variants of lung adenocarcinoma. Lung cancers with wild-type (WT) p53 (LSL-Kras; Ink4a/ARF(FL/FL) mice) responded better to two daily fractions of 7.3 Gy compared to a single fraction of 11.6 Gy (P = 0.002). There was no statistically significant difference in the response of lung cancers deficient in p53 (LSL-Kras; p53(FL/FL) mice) to a single fraction (11.6 Gy) compared to 7.3 Gy × 2 (P = 0.23). Expression of the p53 target genes p21 and PUMA were higher and bromodeoxyuridine uptake was lower after RT in tumors with WT p53.
  
  
  CONCLUSIONS
  Using an in vivo model of malignant lung cancer in mice, we demonstrate that the response of primary lung cancers to one or two fractions of RT can be influenced by specific gene mutations.
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center Durham, NC, USA.
authors.forename: Bradford A
authors.initials: BA
authors.lastname: Perez
authors.forename: A Paiman
authors.initials: AP
authors.lastname: Ghafoori
authors.forename: Chang-Lung
authors.initials: CL
authors.lastname: Lee
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Johnston
authors.forename: Yifan
authors.initials: Y
authors.lastname: Li
authors.forename: Jacob G
authors.initials: JG
authors.lastname: Moroshek
authors.forename: Yan
authors.initials: Y
authors.lastname: Ma
authors.forename: Sayan
authors.initials: S
authors.lastname: Mukherjee
authors.forename: Yongbaek
authors.initials: Y
authors.lastname: Kim
authors.forename: Cristian T
authors.initials: CT
authors.lastname: Badea
authors.forename: David G
authors.initials: DG
authors.lastname: Kirsch
keywords: fractionation; genetically engineered mouse models; p53; tumor cell biology
references.citation: Nat Genet. 2001 Dec;29(4):418-25
references.pmid: 11694875
references.citation: Nature. 2004 Nov 18;432(7015):316-23
references.pmid: 15549093
references.citation: Cancer Cell. 2004 Apr;5(4):375-87
references.pmid: 15093544
references.citation: Oncogene. 2004 Apr 22;23(19):3265-71
references.pmid: 15064735
references.citation: Proc SPIE Int Soc Opt Eng. 2008 Apr 18;6913:691342
references.pmid: 22049304
references.citation: Cancer Res. 1996 Feb 1;56(3):500-6
references.pmid: 8564961
references.citation: Nat Genet. 2005 Jan;37(1):48-55
references.pmid: 15608639
references.citation: Cancer Res. 1998 Sep 1;58(17):3819-25
references.pmid: 9731490
references.citation: Mol Cancer Res. 2011 May;9(5):616-25
references.pmid: 21450905
references.citation: Int J Radiat Oncol Biol Phys. 1999 Jan 15;43(2):399-403
references.pmid: 10030268
references.citation: J Neurosurg. 2006 Jul;105(1):111-8
references.pmid: 16871885
references.citation: Phys Med Biol. 2006 Jul 7;51(13):R263-86
references.pmid: 16790907
references.citation: Nat Rev Cancer. 2003 Feb;3(2):117-29
references.pmid: 12563311
references.citation: Cancer Res. 2005 Nov 15;65(22):10280-8
references.pmid: 16288016
references.citation: Nat Biotechnol. 2010 Jun;28(6):585-93
references.pmid: 20495549
references.citation: Science. 2010 Jan 29;327(5965):593-6
references.pmid: 20019247
references.citation: Sci Signal. 2012 Jul 24;5(234):ra52
references.pmid: 22827996
references.citation: Radiat Res. 2011 Sep;176(3):275-9
references.pmid: 21867429
references.citation: Nature. 2008 Oct 23;455(7216):1069-75
references.pmid: 18948947
references.citation: Int J Radiat Oncol Biol Phys. 1996 Aug 1;36(1):95-103
references.pmid: 8823264
references.citation: Cold Spring Harb Symp Quant Biol. 2005;70:225-32
references.pmid: 16869758
references.citation: Nat Rev Drug Discov. 2006 Sep;5(9):741-54
references.pmid: 16915232
references.citation: Nature. 2012 Mar 18;483(7391):613-7
references.pmid: 22425996
references.citation: Genes Dev. 2010 Apr 15;24(8):837-52
references.pmid: 20395368
references.citation: Br J Radiol. 2010 Jul;83(991):554-68
references.pmid: 20603408
references.citation: Genes Dev. 2003 Dec 15;17(24):3112-26
references.pmid: 14681207
references.citation: Radiat Res. 1996 Mar;145(3):289-98
references.pmid: 8927696
references.citation: Radiat Res. 2007 Jun;167(6):637-44
references.pmid: 17523845
references.citation: Int J Radiat Oncol Biol Phys. 2010 Mar 15;76(4):973-7
references.pmid: 20206017
references.citation: Genes Dev. 2001 Dec 15;15(24):3243-8
references.pmid: 11751630