To the best of our knowledge, this is the first study to demonstrate the mechanism underlying the adaptive resistance to lorlatinib, which involves the HB-EGF/EGFR axis of the ALK-rearranged NSCLC cell line, and to identify the efficacy of combination therapy for EGFR and ALK aimed at tumor eradication in ALK-rearranged lung cancer. The gene discussed is HBEGF; the disease is lung cancer.