ErbB3 plays a key role in the early phase of establishment of resistance to BRAF and/or MEK inhibitors

Luigi Fattore,Maria Rosaria Torrisi,Luigi Aurisicchio,Rita Mancini,Emanuele Marra,Francesca Belleudi,Debora Malpicci,Rosalba Camerlingo,Paolo Antonio Ascierto,Gennaro Ciliberto,Antoni Ribas,Giuseppe Roscilli

doi:10.1186/1479-5876-13-s1-k3

Abstract

Background A major issue in the management of cancer is the development of drug resistance. In metastatic melanoma bearing V600 mutations in the BRAF oncogene, all patients undergo disease relapse after combination therapy with BRAF and MEK inhibitors. Hence, understanding the mechanisms at the basis of development of resistance is fundamental to the discovery of new therapeutic approaches. In our group we have spent the last years to identify mechanisms of early adaptation of BRAF mutated melanoma to BRAF and or MEK inhibitors. We have recently shown that the ErbB3 receptor is involved in the activation of an early feedback survival loop upon cell exposure to BRAF and/or MEK inhibitors. Upregulation of pErbB3, due to enhanced production of its ligand neuregulin-1 (HRG), causes increased AKT phosphorylation and cell survival. Furthermore, we demonstrated that activation of the ErbB3/AKT axis is abrogated by cotreatment with anti-ErbB3 mAbs previously generated in our laboratory.

Highlights

A major issue in the management of cancer is the development of drug resistance
We show that ErbB3 undergoes a strong upregulation of its phosphorylation in the absence of external addition of neuregulin (HRG) upon exposure to vemurafenib or trametinib or both drugs in the 10 out of 11 of cell lines tested
This results in potentiation of growth inhibition and of apoptosis compared to single antibody treatments

Summary

Introduction

A major issue in the management of cancer is the development of drug resistance. In metastatic melanoma bearing V600 mutations in the BRAF oncogene, all patients undergo disease relapse after combination therapy with BRAF and MEK inhibitors. Understanding the mechanisms at the basis of development of resistance is fundamental to the discovery of new therapeutic approaches. In our group we have spent the last years to identify mechanisms of early adaptation of BRAF mutated melanoma to BRAF and or MEK inhibitors. We have recently shown that the ErbB3 receptor is involved in the activation of an early feedback survival loop upon cell exposure to BRAF and/or MEK inhibitors. Upregulation of pErbB3, due to enhanced production of its ligand neuregulin-1 (HRG), causes increased AKT phosphorylation and cell survival. We demonstrated that activation of the ErbB3/AKT axis is abrogated by cotreatment with anti-ErbB3 mAbs previously generated in our laboratory

Methods

Results

Conclusion