BRAF mutant colorectal cancer: ErbB2 expression levels as predictive factor for the response to combined BRAF/ErbB inhibitors

Evelina Miele,Alessandra Vacca,Giuseppina Catanzaro,Agnese Po,Martina Chiacchiarini,Elisabetta Ferretti,Luana Abballe,Gian Paolo Spinelli,Carlo Capalbo,Zein Mersini Besharat

doi:10.1186/s12885-020-6586-0

Abstract

BackgroundColorectal cancer (CRC) is a heterogeneous disease with a complex biology and a wide number of altered genes such as BRAF, KRAS and PIK3CA. Advances with new-targeted therapies have been achieved and available treating options have prolonged patient’s survival. However, BRAF-mutated CRC patients remain unresponsive to available therapies with RAF inhibitors (RAFi) alone or combined with ErbB inhibitors (ErbBi). These unmet needs require further exploitation of oncogenic signaling in order to set up individualized treatments.MethodsTo this end, we tested the efficacy of single agent or combined treatments using the BRAFi, vemurafenib and two different ErbBi: panitumumab and afatinib in CRC cells characterized by different molecular phenotypes.ResultsCombination strategies with BRAFi and ErbBi achieved a better response in BRAFV600E mutated cells expressing high levels of ErbB2.ConclusionsOur findings support the importance of ErbB2 evaluation in BRAF-mutated CRC patients and its role as a positive predictor factor of response to BRAFi/ErbBi combination.

Highlights

Colorectal cancer (CRC) is a heterogeneous disease with a complex biology and a wide number of altered genes such as BRAF, Kirsten RAt Sarcoma (KRAS) and PIK3CA
BRAFV600E CRC cell lines are sensitive to the selective BRAF inhibitor vemurafenib and insensitive to the EGFRinhibitor panitumumab For our investigations, we selected colorectal carcinoma cell lines according to their mutational status (Table 1)
Two (Colo205, HT-29) harbored the BRAFV600E mutation with wild-type epidermal growth factor receptor (EGFR); the third (SW-48) was BRAF wild-type with an EGFR mutation. Both BRAFV600E CRC cell lines are sensitive to the selective BRAF inhibitor vemurafenib and insensitive to the EGFR-inhibitor panitumumab in vitro To explore their in vitro sensitivity to BRAF blockade, we first treated the three CRC cell lines with the selective BRAFV600E inhibitor, vemurafenib (VEM)

Summary

Introduction

Colorectal cancer (CRC) is a heterogeneous disease with a complex biology and a wide number of altered genes such as BRAF, KRAS and PIK3CA. BRAF-mutated CRC patients remain unresponsive to available therapies with RAF inhibitors (RAFi) alone or combined with ErbB inhibitors (ErbBi) These unmet needs require further exploitation of oncogenic signaling in order to set up individualized treatments. Recent studies have shed light on the complex biology of CRC, which reflects its heterogeneous genetic background with alterations involving a variety of genes (e.g., TP53, EGFR, RAS, PIK3CA, BRAF, and PTEN). These efforts have provided fundamental information for the development of novel treatments targeting key signaling pathways in the tumor [2]. These tumors are relatively unresponsive to currently used chemotherapy protocols [6, 7], and in these cases, second-line treatment with anti-epidermal growth factor receptor (EGFR)-antibodies is rarely beneficial [8,9,10]

Methods

Results

Conclusion