Sortilin exhibits tumor suppressor-like activity by limiting EGFR transduction function.

Lung cancer is the leading cause of cancer deaths worldwide and remains one of the most difficult to cure. Tyrosine kinase receptors, such as the epidermal growth factor receptor (EGFR), are often aberrantly activated by gene mutation and drive tumor growth. Monotherapy with tyrosine kinase inhibitors targeting EGFR has shown initial efficacy, but their benefits tend to decline over time. EGFR acts as a transcription factor promoting the expression of oncogenic drivers, which, in turn, cooperate with canonical EGFR mutations to induce therapeutic resistance. This study reports that sortilin, a crucial regulator of cytoplasmic EGFR, attenuates its transducing function. Genome-wide chromatin binding assays revealed that sortilin interacts with gene regulatory elements occupied by EGFR. These results suggest a model in which sortilin exhibits potential tumor suppressor-like activity by concurrently binding to regulatory elements of cMYC. Sortilin expression in lung adenocarcinoma may be predictive of the efficacy of anti-EGFR therapies.