Primary and acquired resistance of colorectal cancer to anti-EGFR monoclonal antibody can be overcome by combined treatment of regorafenib with cetuximab
Menée in vitro et in vivo, cette étude met en évidence des mécanismes suggérant l'intérêt de combiner régorafénib et cétuximab pour surmonter l'apparition d'une résistance aux thérapies ciblées anti-EGFR chez les patients atteints d'un cancer colorectal métastatique
Purpose: In colorectal cancer (CRC) the activation of the intracellular RAS/RAF and PIK3CA/AKT pathways has been implicated in the resistance to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (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. Experimental Design: We have tested, in vitro and in vivo, the effects of regorafenib in a panel of human CRC cell lines with a KRAS mutation (SW480, SW620, HCT116, LOVO, HCT15) or with a BRAF mutation (HT29), as models of intrinsic resistance to cetuximab treatment, and in two human CRC 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). Results: Treatment with regorafenib determined a dose-dependent growth inhibition in all CRC cell lines.The combined treatment with cetuximab and regorafenib induced synergistic anti-proliferative and apoptotic effects in cetuximab-resistant cell lines by blocking MAPK and AKT pathways. Nude mice were injected subcutaneously with HCT116, HCT15, GEO-CRand SW48-CR cells. The combined treatment caused significant tumor growth inhibition. Synergistic antitumor activity of regorafenib plus cetuximab was also observed in an orthotopic CRC model of HCT116 cells. In particular, the combined treatment induceda significant tumor growth inhibition in the primary tumor site (cecum) and completely preventedmetastasis formation. Conclusion:The combined treatment with cetuximab and regorafenib could be a strategy to overcome resistance to anti-EGFR therapies in metastatic CRC patients.