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However, resistance commonly develops, prompting consideration of therapeutic strategies to overcome initial drug resistance mechanisms. This study aimed to elucidate the adaptive resistance to lazertinib and advocate novel combination treatments that demonstrate efficacy in preventing resistance as a first\u2010line treatment for EGFR mutation\u2010positive NSCLC. We found that AXL knockdown significantly inhibited lung cancer cell viability in the presence of lazertinib, indicating that AXL activation contributes to lazertinib resistance. However, long\u2010term culture with a combination of lazertinib and AXL inhibitors led to residual cell proliferation and increased the MCL\u20101 expression level, which was mediated by the nuclear translocation of the transcription factor YAP. Triple therapy with an MCL\u20101 or YAP inhibitor in combination with lazertinib and an AXL inhibitor significantly reduced cell viability and increased the apoptosis rate. These results demonstrate that AXL and YAP\/MCL\u20101 signals contribute to adaptive lazertinib resistance in EGFR\u2010mutant lung cancer cells, suggesting that the initial dual inhibition of AXL and YAP\/MCL\u20101 might be a highly effective strategy in eliminating lazertinib\u2010resistant cells.<\/jats:p>","DOI":"10.1111\/cas.16292","type":"journal-article","created":{"date-parts":[[2024,7,23]],"date-time":"2024-07-23T05:39:35Z","timestamp":1721713175000},"page":"3333-3345","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Initial AXL and MCL\u20101 inhibition contributes to abolishing lazertinib tolerance in EGFR\u2010mutant lung cancer cells"],"prefix":"10.1111","volume":"115","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7850-5330","authenticated-orcid":false,"given":"Yohei","family":"Matsui","sequence":"first","affiliation":[{"name":"Department of Pulmonary Medicine, Graduate School of Medical Science 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