Here, we found that inhibition of BRD4 enhanced osimertinib sensitivity by suppressing YAP1-mediated APT1 transcription and subsequently disrupting MST1 depalmitoylation and the nuclear translocation of YAP1 in NSCLC, revealing a novel mechanism underlying osimertinib resistance. The gene discussed is YAP1; the disease is non-small cell lung carcinoma.