Abstract LB-34: Similar PI3K and RTK-Ras status in patient derived colorectal cancer-xenografts and patients.
Authors: Nunes Manoel , Weiswald Louis-Bastien , Vrignaud Patricia , Vacher Sophie , Turlotte Edouard , Richon Sophie , Bellet Dominique , Roman-Roman Sergio , Bieche Ivan , Dangles-Marie Virginie 
Published: August 2014

There is a recent increase in the use of patient-derived tumor xenografts (PDX) engrafted into immunodeficient mice as improved preclinical models of patient tumors. An important component in the validation of disease-specific PDXs for clinical relevance is comparing the genomic alterations and the response to standard agents. The CReMEC collection of 54 colorectal PDX has been recently reported to mimic the clinical situation for histopathological and molecular diversity of colorectal cancer. We further analyze here this colorectal PDX collection in regard to robust human patient molecular features: 1) Alterations in both PI3K and RTK-Ras pathways; 2) Role of oncogenic activation of EGFR-Ras downstream signaling on response to cetuximab.

The Cancer Genome Atlas Network (TCGA) newly reported a large genome-scale analysis of 276 colorectal cancer tissue samples, showing common genetic alterations in the PI3K and RTK-RAS pathways, with mutual exclusions in the PI3K pathway. The analysis of the PDX panel by CGH array, RNA expression (microarray, real-time qRT-PCR) and exome sequencing confirmed activation with mutual exclusion in PI3K pathway (IGF2 focal amplification/overexpression; IRS2 overexpression, mutation of PIK3CA, PIK3R1 and PTEN homozygous deletion). In RTK-Ras pathway, frequencies of genomic abnormalities (ERBB2 mutation/amplification; mutation of ERBB3, NRAS, KRAS and BRAF) in PDXs are fully in line with the TCGA patient collection.

The response to cetuximab of 52 subcutaneous engrafted PDX (including 24 KRAS mutated PDX) has been analyzed according to translated clinical criteria: xenograft regression as been defined as a partial response (decrease of at least 70% of the tumor volume measured at the beginning of the treatment) or as a complete response. In this unselected population, tumor regression occurred in 8 out of 52 cases (15%); all were KRAS wild type tumors. The percentage of responders was enriched up to 30% (7/23) when PTEN deletion and mutations of KRAS, BRAF, and PIK3CA are concomitantly excluded. These results completely fit with recent publication of data in patients treated with anti-EGFR antibodies.

Taken together, these results demonstrate that colorectal PDXs are representative clinical colorectal tumor models. They also underline their interest as appropriate tools to identify and test new targeted therapeutics.

Citation Format: Manoel Nunes, Louis-Bastien Weiswald, Patricia Vrignaud, Sophie Vacher, Edouard Turlotte, Sophie Richon, Dominique Bellet, Sergio Roman-Roman, Ivan Bieche, Virginie Dangles-Marie. Similar PI3K and RTK-Ras status in patient derived colorectal cancer-xenografts and patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-34. doi:10.1158/1538-7445.AM2013-LB-34