Abstract PR7: Paracrine receptor activation by microenvironment triggers bypass survival signals and ALK inhibitor-resistance in EML4-ALK lung cancer cells

Abstract

Abstract Cancer cell microenvironments, including host cells, can critically affect cancer cell behaviors, including drug sensitivity. We recently reported that hepatocyte growth factor (HGF), the ligand of a tyrosine kinase receptor Met, can be produced not only by cancer cells but also host fibroblasts, activates Met and the downstream PI3K/Akt pathway and triggers resistance to EGFR inhibitors in EGFR mutant lung cancer cells (Yano S et al, Cancer Res, 2008). Crizotinib, a dual inhibitor of ALK and Met, shows dramatic effects against EML4-ALK lung cancer cells, but these cells can acquire resistance by several mechanisms, including ALK amplification and gatekeeper mutation. Although elective ALK inhibitors can overcome crizotinib resistance due to these mechanisms, these cells may become resistant to these inhibitors. Here, we determined whether microenvironmental factors trigger ALK inhibitor resistance in EML4-ALK lung cancer cells. We tested the effects of ligands produced by endothelial cells and fibroblasts, and the cells themselves, on the susceptibility of EML4-ALK lung cancer cell lines to crizotinib and TAE684, a selective ALK inhibitor active against cells with ALK amplification and gatekeeper mutations, both in vitro and in vivo. EML4-ALK lung cancer cells were highly sensitive to ALK inhibitors. EGFR ligands, such as EGF, TGF-α, and HB-EGF, activated EGFR and triggered resistance to crizotinib and TAE684 by transducing bypass survival signaling through Erk1/2 and Akt. HGF activated Met/Gab1 and triggered resistance to TAE684, but not crizotinib, which inhibits Met. Endothelial cells and fibroblasts, which produce the EGFR ligands and HGF, respectively, decreased the sensitivity of EML4-ALK lung cancer cells to crizotinib and TAE684, respectively. EGFR-TKIs re-sensitized these cells to crizotinib and Met-TKI to TAE684 even in the presence of EGFR ligands and HGF, respectively. Our findings suggest that paracrine receptor activation by ligands from the microenvironment may trigger resistance to ALK inhibitors in EML4-ALK lung cancer cells, and provide a rationale for targeting receptor ligands in the microenvironment for more successful treatment with ALK inhibitors. These observation further raise clinical questions which classes ALK inhibitors are more beneficial for EML4-ALK lung cancer patients. This proffered talk is also presented as Poster A30.