Abstract
To improve and focus preclinical testing, we combine tumor models based on a decellularized tissue matrix with bioinformatics to stratify tumors according to stage-specific mutations that are linked to central cancer pathways. We generated tissue models with BRAF-mutant colorectal cancer (CRC) cells (HROC24 and HROC87) and compared treatment responses to two-dimensional (2D) cultures and xenografts. As the BRAF inhibitor vemurafenib is—in contrast to melanoma—not effective in CRC, we combined it with the EGFR inhibitor gefitinib. In general, our 3D models showed higher chemoresistance and in contrast to 2D a more active HGFR after gefitinib and combination-therapy. In xenograft models murine HGF could not activate the human HGFR, stressing the importance of the human microenvironment. In order to stratify patient groups for targeted treatment options in CRC, an in silico topology with different stages including mutations and changes in common signaling pathways was developed. We applied the established topology for in silico simulations to predict new therapeutic options for BRAF-mutated CRC patients in advanced stages. Our in silico tool connects genome information with a deeper understanding of tumor engines in clinically relevant signaling networks which goes beyond the consideration of single drivers to improve CRC patient stratification.
Highlights
Colorectal cancer (CRC) is the third most common cancer worldwide in men, second in women, and 55% of the cases occur in developed countries [1]
For 3D models, HROC24 and HROC87 cell lines were seeded onto the submucosa with preserved mucosa (SISmuc) scaffold derived
3D models, HROC24 were seeded onto the SISmuc derived from For porcine gut and culturedand forHROC87
Summary
Colorectal cancer (CRC) is the third most common cancer worldwide in men, second in women, and 55% of the cases occur in developed countries [1]. About 15% of CRCs develop as a consequence of microsatellite instability (MSI) and represent a specific subgroup of tumors. MSI showed high alteration rates in most of these pathways with most changes occurring in the mitogen-activated protein kinase (MAPK) and Wnt/β-catenin signaling pathways [2]. The activating BRAF missense mutation V600E is part of the MAPK pathway and occurs in. In CRC, the frequency of BRAF V600E mutation is 78% for MSI tumors as compared to only 8% in tumors with chromosomal instability pathway (CIP) [6]. The selective FDA-approved BRAF inhibitor vemurafenib (PLX4032), achieves an impressive clinical response in melanoma [7,8], but fails in most
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