Combined blockade of MEK and PI3KCA as an effective antitumor strategy in HER2 gene amplified human colorectal cancer models

Valentina Belli,Nunzia Matrone,Teresa Troiani,Livio Trusolino,Emilio Francesco Giunta,Umberto Bracale,Francesca Cottino,Giorgia Migliardi,Erika Martinelli,Floriana Morgillo,Andrea Bertotti,Vincenzo De Falco,Fortunato Ciardiello,Davide Ciardiello,Stefania Napolitano

doi:10.1186/s13046-019-1230-z

Abstract

BackgroundTargeting the epidermal growth factor receptor (EGFR) either alone or in combination with chemotherapy is an effective treatment for patients with RAS wild-type metastatic colorectal cancer (mCRC). However, only a small percentage of mCRC patients receive clinical benefits from anti-EGFR therapies, due to the development of resistance mechanisms. In this regard, HER2 has emerged as an actionable target in the treatment of mCRC patients with resistance to anti-EGFR therapy.MethodsWe have used SW48 and LIM1215 human colon cancer cell lines, quadruple wild-type for KRAS, NRAS, BRAF and PI3KCA genes, and their HER2–amplified (LIM1215-HER2 and SW48-HER2) derived cells to perform in vitro and in vivo studies in order to identify novel therapeutic strategies in HER2 gene amplified human colorectal cancer.ResultsLIM1215-HER2 and SW48-HER2 cells showed over-expression and activation of the HER family receptors and concomitant intracellular downstream signaling including the pro-survival PI3KCA/AKT and the mitogenic RAS/RAF/MEK/MAPK pathways. HER2-amplified cells were treated with several agents including anti-EGFR antibodies (cetuximab, SYM004 and MM151); anti-HER2 (trastuzumab, pertuzumab and lapatinib) inhibitors; anti-HER3 (duligotuzumab) inhibitors; and MEK and PI3KCA inhibitors, such as refametinib and pictilisib, as single agents and in combination. Subsequently, different in vivo experiments have been performed. MEK plus PI3KCA inhibitors treatment determined the best antitumor activity. These results were validated in vivo in HER2-amplified patient derived tumor xenografts from three metastatic colorectal cancer patients.ConclusionsThese results suggest that combined therapy with MEK and PI3KCA inhibitors could represent a novel and effective treatment option for HER2-amplified colorectal cancer.

Highlights

Targeting the epidermal growth factor receptor (EGFR) either alone or in combination with chemotherapy is an effective treatment for patients with RAS wild-type metastatic colorectal cancer
Western blot analysis showed an increased expression and phosphorylation of EGFR, Human epidermal growth factor receptor 3 (HER3) and Human epidermal growth factor receptor 4 (HER4) in Human epidermal growth factor receptor 2 (HER2)-amplified derivatives, that could lead to a complex intracellular signaling which includes the activation of the pro-survival Phosphatidylinositol 4 (PI3KCA)/AKT pathway and of the mitogenic mitogen-activated protein kinase (MAPK) pathway [31, 32]
Antitumor efficacy of oxaliplatin plus trastuzumab followed by maintenance treatment with different inhibitors alone or in combination with trastuzumab in HER2-amplified human cancer xenografts In a subsequent in vivo experiment, two groups of 90 nude mice were injected subcutaneously with each HER2-amplified cancer cells and were treated for 4 weeks with the combination of oxaliplatin plus trastuzumab

Summary

Introduction

Targeting the epidermal growth factor receptor (EGFR) either alone or in combination with chemotherapy is an effective treatment for patients with RAS wild-type metastatic colorectal cancer (mCRC). At least one third of mCRC patients with RAS wild type tumors receiving first-line chemotherapy in combination with anti-EGFR mAbs fail to have a therapeutic response These results indicate that additional genetic alterations in genes implicated in the EGFR signaling network can be involved in the primary resistance [5,6,7,8]. In these preclinical models of human colorectal cancer, the combination of an anti-HER2 antibody (pertuzumab or trastuzumab) and an HER2 tyrosine kinase inhibitor (TKI) (lapatinib) induced pronounced tumor shrinkage [17] These preclinical results were the proof of concept for clinical trials targeting HER2 genetic alterations in mCRC patients [22]. Understanding the mechanisms of resistance to HER2 blockade is a priority to develop more effective and additional options for therapy in this disease setting

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Results

Discussion

Conclusion