Model-based analysis of response and resistance factors of cetuximab treatment in gastric cancer cell lines.

Elba Raimúndez,Birgit Luber,Jan Hasenauer,Fabian J. Theis,Dieter Maier,Karolin Ebert,Gwen Zwingenberger,Sabine Hug,Simone Keller,James Gallo

doi:10.1371/journal.pcbi.1007147

Abstract

Targeted cancer therapies are powerful alternatives to chemotherapies or can be used complementary to these. Yet, the response to targeted treatments depends on a variety of factors, including mutations and expression levels, and therefore their outcome is difficult to predict. Here, we develop a mechanistic model of gastric cancer to study response and resistance factors for cetuximab treatment. The model captures the EGFR, ERK and AKT signaling pathways in two gastric cancer cell lines with different mutation patterns. We train the model using a comprehensive selection of time and dose response measurements, and provide an assessment of parameter and prediction uncertainties. We demonstrate that the proposed model facilitates the identification of causal differences between the cell lines. Furthermore, our study shows that the model provides predictions for the responses to different perturbations, such as knockdown and knockout experiments. Among other results, the model predicted the effect of MET mutations on cetuximab sensitivity. These predictive capabilities render the model a basis for the assessment of gastric cancer signaling and possibly for the development and discovery of predictive biomarkers.

Highlights

Gastric cancer is the fifth most common cancer and third leading cause of death from cancer worldwide [1]
We found that the model provides reasonable predictions for long-time response of epidermal growth factor receptor (EGFR), Phosphorylated EGFR (pEGFR) and Phosphorylated ERK (pERK) (Fig 5D)
We found that the model provides accurate quantitative predictions for EGFR, pEGFR, pERK and phosphorylated AKT (pAKT) (Fig 6C and S9 Fig) (Pearson correlation ρ = 0.872) the down-regulation of pERK is slightly underestimated

Summary

Introduction

Gastric cancer is the fifth most common cancer and third leading cause of death from cancer worldwide [1]. The EGFR antibody cetuximab did not improve patient survival in a phase III clinical trial [4]. EGFR is overepressed in many cancer types and activated by a variate of ligands [6], including besides EGF the transforming growth factor-alpha (TGFA), heparin-binding EGF-like growth factor (HBEGF), betacellulin (BTC), amphiregulin (AREG) and epiregulin (EREG) and epigen (EPGN). All these ligands bind to EGFR in the abscence of cetuximab, they do not produce identical biological responses. Cetuximab induces antibody-dependent cellular cytotoxicity (ADCC) by provoking immune cells to attack cancer cells [8]

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