EGFR activation elicited adaptive resistance to lorlatinib in ALK-rearranged non-small cell lung cancer cells

Anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs), including lorlatinib have shown dramatic efficacy in patients with ALK-rearranged lung cancer; however, complete response in these patients is rare. In this preclinical study, we investigated the adaptive resistant mechanisms to lorlatinib and its therapeutic strategies to overcome, using in vitro and in vivo experiments. Cell line-based assay showed that exposure of lorlatinib accelerated EGFR signal activation as an adaptive response via activation of JNK cascade in ALK- rearranged lung cancer cells. Knockdown for EGFR suppressed the survival signal of ALK lung cancer cells when treated with lorlatinib. The combination of lorlatinib and erlotinib, a first-generation EGFR-TKI, was shown to enhance cell growth inhibition by inducing cell apoptosis via suppressing the anti-apoptotic factor Bcl-xl compared with lorlatinib monotherapy. Moreover, cell line-derived xenograft model indicated that the combination of lorlatinib plus erlotinib enhanced anti-tumor effects compared with lorlatinib monotherapy. Taken together, our results displayed that EGFR activation plays an important role in the initial adaptive resistance to lorlatinib for ALK-rearranged lung cancer. The combination of lorlatinib and erlotinib is expected as the promising strategy for those tumors.