Abstract 3932: p53 mutation cooperates with Rb loss to promote aggressive metastatic small cell lung cancer in the absence of gain-of-function effects
Authors: Akeno Nagako , Greaves Rebecca , Miller Ashley L. , Wikenheiser-Brokamp Kathryn A. 
Published: May 2015

Lung cancer is divided into non-small cell (NSCLC) and small cell lung cancer (SCLC) based upon distinct morphologic and biologic characteristics as well as markedly different patient presentations and treatments. Despite these differences in tumor biology and clinical characteristics, p53 mutation and loss of Rb function are detected in &gt;70% of NSCLC and SCLC providing evidence that p53 and Rb are critical tumor suppressors in both lung cancer subtypes. Missense p53 mutations can confer dominant negative or gain-of-function properties that promote carcinogenesis. The occurrence frequency of the common p53 mutations, R275H and R175H (R270H and R172H in the mouse), differs between NSCLC and SCLC; the mutations occurring with equal frequency in SCLC and R275H mutations being more frequently detected than R175H mutations in NSCLC. In the present study, p53 loss or mutation was targeted to Rb deficient pulmonary airway epithelium in a conditional mouse model using the rat Clara Cell Secretory Protein (CCSP) promoter to determine whether Rb and p53 have cell type specific functions critical for suppressing lung carcinogenesis. Combined Rb/p53 ablation uniformly resulted in metastatic high grade neuroendocrine carcinomas that phenotypically mimic human SCLC and result in death by a median 6 months of age. Surprisingly, only 1/7 (14%) of the mice developed NSCLC despite targeting non-neuroendocrine cell lineages believed to give rise to NSCLC. Mice mated to the ROSA26 reporter strain wherein ß-galactosidase expression marks targeted cells were used to demonstrate that a subpopulation of neuroendocrine cells, the cell of origin for SCLC, was also targeted in this model as indicated by coexpression of ß-galactosidase in 6% of cells expressing the neuroendocrine cell marker, calcitonin gene related peptide. Interestingly, targeted expression of the p53 R270H and R172H mutant proteins in Rb deficient pulmonary airway epithelial cells resulted in a similar phenotype as mice with Rb/p53 deficient lungs. Mice with Rb deficient/p53 mutant expressing lung epithelium uniformly developed metastatic SCLC resulting in death by a median of 5.5 months and 5 months of age, respectively. No NSCLC were detected in Rb deficient/p53 mutant lungs. Together, these data demonstrate that Rb and p53 have cooperative, cell lineage specific functions critical for suppressing lung carcinogenesis and that p53 loss and mutation have similar biologic effects in Rb deficient airway epithelium. In addition to providing mechanistic insights, this clinically relevant genetically engineered mouse model provides a robust platform to explore novel therapeutics as well as define mechanisms underlying treatment response and resistance.

Citation Format: Nagako Akeno, Rebecca Greaves, Ashley L. Miller, Kathryn A. Wikenheiser-Brokamp. p53 mutation cooperates with Rb loss to promote aggressive metastatic small cell lung cancer in the absence of gain-of-function effects. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3932. doi:10.1158/1538-7445.AM2014-3932