L3MBTL1, a polycomb protein, promotes Osimertinib Acquired resistance through Epigenetic Regulation of DNA damage response in lung adenocarcinoma

Osimertinib is a third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (EGFR-TKI) that was approved for patients with EGFR T790M resistance mutations as first- or second-line treatment for EGFR-positive patients. Resistance to Osimertinib inevitably develops and the underlying mechanisms are largely unknown. In this study, we discovered that acquired resistance to Osimertinib is linked to an abnormal DNA damage response (DDR) and chromatin remodeling in lung adenocarcinoma cells. We found that the polycomb protein Lethal(3) Malignant Brain Tumor-Like Protein 1 (L3MBTL1) is involved in the DDR and Osimertinib resistance by regulating chromatin structure. EGFR oncogene inhibition reduced L3MBTL1 ubiquitination and stabilized its expression in Osimertinib-resistant cells. L3MBTL1 reduction combined with Osimertinib treatment significantly inhibited DNA damage, proliferation, and invasion of Osimertinib-resistant lung cancer cells in vitro and in vivo. L3MBTL1 binds to histones throughout the genome and plays a critical role in EGFR-TKI resistance, which also competes with 53BP1 binding to H4K20Me2 and inhibits the development of drug resistance in Osimertinib-resistant lung cancer cells in vitro and in vivo. Our findings indicate that L3MBTL1 inhibition represents a novel approach to circumvent EGFR-TKI acquired resistance.