Dual targeting of HER3 and MEK may overcome HER3-dependent drug-resistance of colon cancers.

Giulia Bon,Rossella Loria,Rita Falcioni,Matilde Todaro,Arianna Mastrofrancesco,Michele Milella,Carla Azzurra Amoreo,Marcella Mottolese,Maria Grazia Diodoro,Giorgio Stassi,Alessandra Verdina,Ruggero De Maria,Silvia Soddu,Isabella Sperduti

doi:10.18632/oncotarget.11400

Abstract

Although the medical treatment of colorectal cancer has evolved greatly in the last years, a significant portion of early-stage patients develops recurrence after therapies. The current clinical trials are directed to evaluate new drug combinations and treatment schedules.By the use of patient-derived or established colon cancer cell lines, we found that the tyrosine kinase receptor HER3 is involved in the mechanisms of resistance to therapies. In agreement, the immunohistochemical analysis of total and phospho-HER3 expression in 185 colorectal cancer specimens revealed a significant correlation with lower disease-free survival.Targeting HER3 by the use of the monoclonal antibody patritumab we found induction of growth arrest in all cell lines. Despite the high efficiency of patritumab in abrogating the HER3-dependent activation of PI3K pathway, the HER2 and EGFR-dependent MAPK pathway is activated as a compensatory mechanism. Interestingly, we found that the MEK-inhibitor trametinib inhibits, as expected, the MAPK pathway but induces the HER3-dependent activation of PI3K pathway. The combined treatment results in the abrogation of both PI3K and MAPK pathways and in a significant reduction of cell proliferation and survival.These data suggest a new strategy of therapy for HER3-overexpressing colon cancers.

Highlights

Colorectal cancer (CRC) is the third most frequent cancer in males and the second in females
By the use of patient-derived or established colon cancer cell lines, we found that the tyrosine kinase receptor HER3 is involved in the mechanisms of resistance to therapies
All cell lines were characterized for the mutations of BRAF, KRAS, and PIK3CA oncogenes, for the status of p53 (Supplementary Table S1), and for the expression of EGFR family members, whose expression and activity has been described strictly correlated with the responsiveness to therapy (Supplementary Figure S1) [10,11, 37]

Summary

Introduction

Colorectal cancer (CRC) is the third most frequent cancer in males and the second in females. The current treatment for CRC is based on combination therapies that in most cases include surgery, local radiotherapy and chemotherapy. The development of drug resistance still occurs in a great number of patients determining recurrence. Several current clinical trials are directed to evaluate new drug combinations, in order to enhance tumor regression, increase overall survival, and improve the quality of life for CRC patients. We provide evidence of the crucial role played by the tyrosine kinase receptor HER3 in the development of resistance to 5-FU and Ox treatments in CRC cells. HER3 overexpression has been reported in 50–70% of cases [6,7,8] and seems to be associated with metastasis [8], tumor size, and risk of local recurrence [9]. Increased HER3 mRNA or protein is commonly seen in colon carcinomas and is associated with lymph node metastasis and a shorter time to progression [12,13,14,15]

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Conclusion