Colon cancers carrying BRAF V600E and β-catenin T41A activating mutations are resistant to numerous common anticancer drugs.

Abstract

Colorectal cancer is a common malignancy with a high prevalence and associated mortality rate. However, the preclinical tools currently used for drug development are insufficient. The aim of the present study was to establish and characterize a specific patient-derived colon cancer xenograft (PDCCX) mouse model for drug testing. Primary colon tumors were obtained from 10 patients by surgical resection, and tumor tissues were subsequently grafted into nude mice followed by consecutive passages. Primary tumors and xenograft tumors were collected and processed for DNA sequencing, histological evaluation and immunohistochemical staining. The responses of fifth-generation PDCCX mice to 5-fluorouracil, oxaliplatin, and cetuximab were assessed. Two PDCCX cell lines were successfully established. The histology and protein expression levels of SMAD family member 3, epidermal growth factor receptor, c-MET, caudal type homeobox 2, E-cadherin and β-catenin in the xenograft tumors were consistently maintained from the primary cancer tissues. BRAF V600E and β-catenin T41A double mutations were identified in one cell line, and were associated with a lack of response to 5-fluorouracil, oxaliplatin and cetuximab treatment. This PDCCX cell line may provide a reliable tool for preclinical evaluation of the efficacy of novel therapies that may target the BRAF V600E and β-catenin mutations.