mTOR inhibition activates the EGFR-MAPK network by a novel AKT-initiated feedback loop promoting adaptive resistance

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer globally, resulting in more than 300,000 deaths each year worldwide. Treatment options for HNSCC patients include surgery, radiation, chemotherapy, and molecularly targeted therapies, and although immunotherapies have recently revolutionized the treatment landscape, <20% of HNSCC patients respond to immune checkpoint blockade (ICB) therapies. The survival rate of HNSCC patients has changed only modestly over the past decades, and therefore, HNSCC is a significant global health problem with high mortality and morbidity. Genomic alterations converging on persistent activation of the PI3K/mTOR pathway (>80% of cases) represent one of the most frequently altered signaling circuits in HNSCC. This overreliance on PI3K/mTOR signaling for tumor growth may expose a cancer vulnerability that can be therapeutically exploited, as revealed by recent clinical trials of mTOR inhibitors (mTORi) in HNSCC in the adjuvant and neoadjuvant settings. However, mTORi are ineffective in patients with advanced HNSCC, highlighting the urgency of elucidating the mechanisms underlying mTORi resistance. By combining the power of systems biology and computational approaches, including a high-throughput kinase activity mapping strategy, CRISPR/Cas9 synthetic lethal screening, CRISPR-guided GFP-tagging of endogenous EGFR, and the analysis of the spatiotemporal activation of intracellular ERK pools, we have now identified the activation of EGFR-MAPK signaling induced by mTORi in HNSCC as a major adaptive compensatory resistance pathway. Mechanistically, we found that mTOR inhibition activates the EGFR-MAPK pathway by disrupting a novel AKT-regulated feedback loop that inactivates EGFR. Ultimately, our findings suggest that the adaptive activation of EGFR represents a new mechanism of mTORi resistance, and that EGFR co-targeting may be a potent therapeutic option for HNSCC. These findings may be relevant to a large number of cancer types that depend on PI3K/mTOR signaling but fail to respond to mTORi therapies as single agents.