Abstract 1668: Effective targeting of colorectal cancer with a recombinant antibody mixture against EGFR, HER3 and IGF1R

Abstract

Abstract The epidermal growth factor receptor (EGFR) plays an important role in the development and maintenance of the malignant phenotype of several human cancers. Therefore, it is a frequently pursued therapeutic target and several antibodies targeting EGFR have been clinically approved. However, the clinical responses to current anti-EGFR agents are often modest, indicating a need for improved therapeutics. Resistance mechanisms to anti-EGFR antibodies include ligand up-regulation, receptor tyrosine kinase plasticity, and mutations in downstream signaling molecules such as KRAS, BRAF, and PIK3CA. Here, we present data showing that a mixture of antibodies targeting HER3, EGFR, and IGF1R (HEI mixture) with high affinity ligand-blocking antibodies induced growth inhibition in a large panel of cancer cell lines. Synergies of simultaneous inhibition of the three targets were frequently seen in cell lines and xenograft tumor models. In particular, colorectal cancer cell lines were sensitive to the HEI mixture and superiority to cetuximab was seen in several cell lines. Surprisingly, the HEI mixture was effective at inhibiting the growth of KRAS and BRAF mutated cell lines, suggesting that the three receptor tyrosine kinases may still contribute to the malignant phenotype of tumors with these genomic alterations. Colorectal cancer is thought to be a ligand driven disease and hence the inhibitory activity of the HEI mixture was tested in the presence of EGFR, HER3 and IGF1R ligands and compared with the activity of cetuximab. As expected, the HEI mixture was able to block growth stimulation induced by all ligands, whereas heregulin and IGF1/IGF2 caused resistance to cetuximab. A clinically relevant subpopulation of colorectal cancer harbors amplification of IGF2, a major ligand for IGF1R, and hence should display sensitivity to IGF1R targeting. The HEI mixture was tested in three metastatic colorectal PDX models with IGF2 overexpression and induced tumor regression in all three models. In conclusion, our data indicate that simultaneous targeting of EGFR, HER3 and IGFR1 provides a broader efficacy than targeting a single receptor, and thereby provides a rationale for simultaneous targeting of the three receptors with a recombinant antibody mixture. Citation Format: Christina Egebjerg, Camilla Fröhlich, Karsten Wessel Eriksen, Thomas Tuxen Poulsen, Klaus Kofoed, Thomas Bouquin, Andrea Bretotti, Livio Trusolino, Ivan David Horak, Michael Kragh, Mikkel Wandahl Pedersen. Effective targeting of colorectal cancer with a recombinant antibody mixture against EGFR, HER3 and IGF1R. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1668. doi:10.1158/1538-7445.AM2015-1668