AXL‐Mediated Drug Resistance in ALK‐Rearranged NSCLC Enhanced by GAS6 From Macrophages and MMP11 Positive Fibroblasts

• DOI: 10.1111/cas.70006
• Publication Date: 2025-02-05T00:39:06Z
• Authors: Takahiro Utsumi; Hayato Mizuta; Yosuke Seto; Ken Uchibori; Makoto Nishio; Isamu Okamoto; Ryohei Katayama
• Keywords: GAS6; Alectinib

ABSTRACT Anaplastic lymphoma kinase (ALK) rearranged non‐small cell lung cancer (NSCLC) shows marked tumor shrinkage by ALK‐tyrosine inhibitors (TKIs). However, tumors almost inevitably relapse owing to the development of acquired resistance. Resistance mechanisms include secondary ALK mutations and activation bypass pathways, such as cMET, cKIT, or EGFR, though some remain unknown. In this study, we analyzed alectinib‐resistant patient samples identified a significant increase in AXL expression tumor, high level GAS6, ligand for AXL, pleural effusion. AXL‐overexpressing H3122 ALK‐rearranged NSCLC cells exhibited partial resistance alectinib, which was enhanced GAS6 supplementation but could be overcome ALK/AXL inhibitor gilteritinib. Moreover, GAS6‐overexpressing NIH3T3 AXL‐expressing were subcutaneously injected into left right sides nude mice simultaneously, followed alectinib treatment. The supply from may have accelerated under even without NIH3T3, relapsed within 1 month possibly due increased host mouse Gas6 expression. Single‐cell RNA sequencing revealed that specific cancer‐associated fibroblasts (CAFs) subset tumor‐associated macrophages (TAMs) are primary sources microenvironment (TME). During treatment, TAMs their infiltration TME, whereas CAFs altered patterns, substantially upregulating Mmp11. These findings suggest resistant cells, combined with production contributes ALK‐TKI