Assessing the radiation response of lung cancer with different gene mutations using genetically engineered mice.

Perez, Bradford A

Ghafoori, A Paiman

Lee, Chang-Lung

Johnston, Samuel M

Li, Yifan

Moroshek, Jacob G

Ma, Yan

Mukherjee, Sayan

Kim, Yongbaek

Badea, Cristian T

Kirsch, David G

Switzerland

2018-03-06T11:59:20Z

2018-03-06T11:59:20Z

2013

PURPOSE: 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). MATERIALS AND 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. CONCLUSION: 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.

https://www.ncbi.nlm.nih.gov/pubmed/23565506

2234-943X

https://hdl.handle.net/10161/16172

eng

Frontiers Media SA

Front Oncol

10.3389/fonc.2013.00072

fractionation

genetically engineered mouse models

p53

tumor cell biology

Assessing the radiation response of lung cancer with different gene mutations using genetically engineered mice.

Journal article

Lee, Chang-Lung|0000-0002-0673-633X

Badea, Cristian T|0000-0002-1850-2522

https://www.ncbi.nlm.nih.gov/pubmed/23565506

72

Basic Science Departments

Clinical Science Departments

Duke

Duke Cancer Institute

Institutes and Centers

Pharmacology & Cancer Biology

Radiation Oncology

Radiology

School of Medicine

Published online

3