Imaging inhibition of the Warburg effect by the EGFR inhibitor Cetuximab in patient-derived Head and Neck xenografts

Mignion, Lionel [UCL] Acciardo, Stefania [UCL] Joudiou, Nicolas [UCL] Caignet, Xavier [UCL] Goebbels, Rose-Marie Schmitz, Sandra [UCL] Machiels, Jean-Pascal [UCL] Jordan, Bénédicte [UCL]

PURPOSE: Optimal Head and Neck Squamous Cell Carcinoma (HNSCC) patient selection for anti-EGFR-based therapy remains an unmet need since only a minority of patients derive long-term benefit from cetuximab treatment. We assessed the ability of state-of-the art non-invasive in vivo metabolic imaging to probe metabolic shift in cetuximab-sensitive and resistant HNSCC patient-derived xenografts (PDTX). EXPERIMENTAL DESIGN: Three models selected based on their known sensitivity to cetuximab in patients (cetuximab-sensitive or acquired-resistant HNC007 PDTX, cetuximab-naïve UCLHN4 PDTX, and cetuximab-resistant HNC010 PDTX), were inoculated in athymic nude mice. RESULTS: Cetuximab induced tumor size stabilization in mice for 4 weeks in cetuximab-sensitive and naïve models treated with weekly injections (30mg/kg) of cetuximab. Hyperpolarized 13C-pyruvate -13C-lactate exchange was significantly decreased in vivo in cetuximab-sensitive xenograft models 8 days after treatment initiation, whereas it was not modified in cetuximab-resistant xenografts. Ex vivo analysis of sensitive tumors resected at day 8 post-treatment highlighted specific metabolic changes, likely to participate in the decrease in the lactate to pyruvate ratio in vivo Diffusion MRI showed a decrease in tumor cellularity in the HNC007 sensitive tumors, but failed to show sensitivity to cetuximab in the UCLHN4 model. CONCLUSIONS: This study constitutes the first in vivo demonstration of cetuximab-induced metabolic changes in cetuximab-sensitive HNSCC PDTX that were not present in resistant tumors. Using metabolic imaging, we were able to identify hyperpolarized 13C-pyruvate as a potential marker for response and resistance to the EGFR inhibitor in HNSCC.