Abstract LB-C25: Inhibition of ERBB3 with MM-121, IGF1-R with MM-141 or Met with MM-131 increases the activity of EGFR inhibitor MM-151 in colorectal cancer models expressing multiple resistance ligands
Authors: Wainszelbaum Marisa J. , Fessler Jessica , Lahdenranta Johanna , Burenkova Olga , Gerami-Moayed Nat , Hashambhoy-Ramsay Yasmin , Rimkunas Victoria , MacBeath Gavin 
Published: May 2016

Abstract
Introduction: The Epidermal Growth Factor Receptor (EGFR) pathway is a key driver of late-stage colorectal cancer (CRC) and EGFR inhibitors, such as cetuximab and panitumumab, prolong survival in a large subset of patients. Not all patients respond to EGFR inhibitor therapy, however, and resistance develops in those who respond. Accumulating evidence suggests that alternative signaling pathways circumvent EGFR blockade. Several studies have shown that tumors with high heregulin, IGF-1 or HGF respond poorly to EGFR-targeted therapies. Further, Phase 2 studies suggest that combined inhibition of EGFR and HGF with panitumumab and rilotumumab significantly improves response rates compared to panitumumab alone. These data support the notion that more than one pathway may be simultaneously active in late-stage CRC and that EGFR-directed therapy may be improved through combination strategies.
Merrimack has built a portfolio of biologic agents targeting key oncogenic receptors that block ligand binding and pathway activation, providing a unique opportunity to develop combination therapies in a biomarker-driven fashion. MM-151 targets EGFR; MM-121 (seribantumab) targets ERBB3; MM-141 (istiratumab) targets both IGF-1R and ERBB3; and MM-131 targets Met and EpCAM. Here we investigate responsiveness to different resistance ligands and the ability of drug combinations to block ligand-mediated cell growth more effectively than monotherapy.
Experimental procedures: We evaluated the prevalence of resistance ligands in colorectal adenocarcinoma patient samples by RNA in situ hybridization. To assess the effect of ligands and drugs on cell growth we assembled a panel of 29 genetically diverse CRC cell lines. Using a carefully optimized in vitro 3D culture system, we measured cell viability in response to MM-151, MM-121, MM-141, MM-131 or a combination of the drugs using MM-151 as the backbone. The screen was performed in the presence or absence of exogenously added ligands: EGF, heregulin, IGF-1 or HGF. Using these data, we selected representative xenograft models for in vivo analysis of drug combination efficacy.
Results: We show that colorectal cancer tumors co-express resistance ligands and that ligand prevalence appears to increase following treatment. Results from our in vitro screen show that CRC cell lines fall into two groups: those that are unresponsive to ligand stimulation and those that are responsive. Interestingly, cell lines that are responsive to one ligand tend to respond to other ligands as well, suggesting that blocking more than one pathway may prove more effective than blocking only a single pathway. In pre-clinical models of cell lines and xenografts, where ligands are co-expressed, combinations of targeted antibodies, using MM-151 as the backbone, have greater activity than monotherapy.
Conclusions: These data suggest that subsets of patients with high expression of individual or multiple ligands could benefit from different combinations of targeted therapies. A Phase 1 study evaluating the safety, pharmacology and preliminary activity of the co-administration of MM-151 and MM-121 (seribantumab) in heregulin positive cancer patients is currently enrolling patients with advanced colorectal cancer, non-small cell lung cancer, and head and neck cancer.
Citation Format: Marisa J. Wainszelbaum, Jessica Fessler, Johanna Lahdenranta, Olga Burenkova, Nat Gerami-Moayed, Yasmin Hashambhoy-Ramsay, Victoria Rimkunas, Gavin MacBeath. Inhibition of ERBB3 with MM-121, IGF1-R with MM-141 or Met with MM-131 increases the activity of EGFR inhibitor MM-151 in colorectal cancer models expressing multiple resistance ligands. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-C25.