We hypothesized that L3MBTL1 primarily compacts chromatin by combining with H4K20Me2 in EGFR-TKI-acquired drug-resistant lung cancer cells, because 53BP1 did not bind to H4K20Me2, reducing DNA damage after Osimertinib treatment of Osimertinib-resistant cells. Here, EGFR is linked to lung carcinoma.