无论是ALK-TKI还是鲁拉替尼，治疗具有高度混合表型的ALK重排非小细胞肺癌（NSCLC）患者时，均很少能引发完全的临床反应，因为一小部分肿瘤细胞由于适应性抗性而存活。因此，我们关注了适应性抗性机制和治疗策略。我们发现，表皮生长因子受体（EGFR）信号参与ALK重排NSCLC对鲁拉替尼的适应性抗性，被诱导出来的是通过c-Jun激活引起的葡萄糖酸苷酰基乙酰化酶类2（HBEGF）表现的神经营养因子。EGFR抑制通过抑制Bcl-xL增强ALK抑制诱导的细胞凋亡停止ALK重排肺癌细胞的增殖。Xenograft模型证实，EGFR抑制剂和鲁拉替尼的组合可显著抑制治疗终止后的肿瘤再生长。本研究提供了关于鲁拉替尼治疗后肿瘤演变的EGFR信号通路方面的新见解和ALK重排肺癌的联合治疗策略。© 2023. 作者。

Anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitors rarely elicit complete responses in patients with advanced ALK-rearranged non-small cell lung cancer (NSCLC), as a small population of tumor cells survives due to adaptive resistance. Therefore, we focused on the mechanisms underlying adaptive resistance to lorlatinib and therapeutic strategies required to overcome them. We found that epidermal growth factor receptor (EGFR) signaling was involved in the adaptive resistance to lorlatinib in ALK-rearranged NSCLC, activation of which was induced by heparin-binding EGF-like growth factor production via c-Jun activation. EGFR inhibition halted ALK-rearranged lung cancer cell proliferation by enhancing ALK inhibition-induced apoptosis via suppression of Bcl-xL. Xenograft models showed that the combination of EGFR inhibitor and lorlatinib considerably suppressed tumor regrowth following cessation of these treatments. This study provides new insights regarding tumor evolution due to EGFR signaling after lorlatinib treatment and the development of combined therapeutic strategies for ALK-rearranged lung cancer.© 2023. The Author(s).