TGF-α and amphiregulin paracrine network promotes resistance to EGFR blockade in colorectal cancer cells.

PURPOSE: Targeted inhibition of EGFR with the mAbs cetuximab or panitumumab is a valuable treatment for RAS wild-type colorectal cancers. The efficacy of EGFR blockade is limited by the emergence of acquired resistance often attributed to secondary KRAS mutations. Remarkably, tumor biopsies from resistant patients show that only a fraction of the resilient cells carry KRAS mutations. We hypothesized that a paracrine cross-talk driven by the resistant subpopulation may provide in trans protection of surrounding sensitive cells. EXPERIMENTAL DESIGN: Conditioned medium assays and three-dimensional cocultures were used to assess paracrine networks between cetuximab-sensitive and -resistant cells. Production of EGFR ligands by cells sensitive to cetuximab and panitumumab was measured. The ability of recombinant EGFR ligands to protect sensitive cells from cetuximab was assessed. Biochemical activation of the EGFR signaling pathway was measured by Western blotting. RESULTS: Colorectal cancer cells sensitive to EGFR blockade can successfully grow despite cetuximab treatment when in the company of their resistant derivatives. Media conditioned by resistant cells protect sensitive parental cells from cetuximab. EGFR blockade triggers increased secretion of TGFα and amphiregulin. Increased secretion of ligands by resistant cells can sustain EGFR/ERK signaling in sensitive cells. CONCLUSIONS: Colorectal cancer cells that develop resistance to cetuximab and panitumumab secrete TGFα and amphiregulin, which protect the surrounding cells from EGFR blockade. This paracrine protective mechanism might be therapeutically exploitable.