Skip to Content
Merck
  • Primary and Acquired Resistance of Colorectal Cancer to Anti-EGFR Monoclonal Antibody Can Be Overcome by Combined Treatment of Regorafenib with Cetuximab.

Primary and Acquired Resistance of Colorectal Cancer to Anti-EGFR Monoclonal Antibody Can Be Overcome by Combined Treatment of Regorafenib with Cetuximab.

Clinical cancer research : an official journal of the American Association for Cancer Research (2015-04-04)
Stefania Napolitano, Giulia Martini, Barbara Rinaldi, Erika Martinelli, Maria Donniacuo, Liberato Berrino, Donata Vitagliano, Floriana Morgillo, Giusy Barra, Raffaele De Palma, Francesco Merolla, Fortunato Ciardiello, Teresa Troiani
ABSTRACT

In colorectal cancer, the activation of the intracellular RAS-RAF and PIK3CA-AKT pathways has been implicated in the resistance to anti-EGFR mAbs. We have investigated the role of regorafenib, an oral multikinase inhibitor, in combination with cetuximab, an anti-EGFR mAb, to overcome anti-EGFR resistance. We have tested, in vitro and in vivo, the effects of regorafenib in a panel of human colorectal cancer cell lines with a KRAS mutation (SW480, SW620, HCT116, LOVO, and HCT15) or with a BRAF mutation (HT29), as models of intrinsic resistance to cetuximab treatment, and in two human colorectal cancer cell lines (GEO and SW48) that are cetuximab-sensitive, as well as in their derived cells with acquired resistance to cetuximab (GEO-CR and SW48-CR). Treatment with regorafenib determined a dose-dependent growth inhibition in all colorectal cancer cell lines. The combined treatment with cetuximab and regorafenib induced synergistic antiproliferative and apoptotic effects in cetuximab-resistant cell lines by blocking MAPK and AKT pathways. Nude mice were injected s.c. with HCT116, HCT15, GEO-CR, and SW48-CR cells. The combined treatment caused significant tumor growth inhibition. Synergistic antitumor activity of regorafenib plus cetuximab was also observed in an orthotopic colorectal cancer model of HCT116 cells. In particular, the combined treatment induced a significant tumor growth inhibition in the primary tumor site (cecum) and completely prevented metastasis formation. The combined treatment with cetuximab and regorafenib could be a strategy to overcome resistance to anti-EGFR therapies in metastatic colorectal cancer patients.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
1,1,2,2-Tetrabromoethane, 98%
Sigma-Aldrich
1,1,2,2-Tetrabromoethane, SAJ first grade, ≥98.0%
Sigma-Aldrich
Anti-α-Tubulin antibody, Mouse monoclonal, clone AA13, purified from hybridoma cell culture