In:
Cancer Science, Wiley
Abstract:
Gilteritinib is a multitarget tyrosine kinase inhibitor (TKI), approved for the treatment of FLT3‐mutant acute myeloid leukemia, with a broad range of activity against several tyrosine kinases including anaplastic lymphoma kinase (ALK). This study investigated the efficacy of gilteritinib against ALK ‐rearranged non‐small cell lung cancers (NSCLC). To this end, we assessed the effects of gilteritinib on cell proliferation, apoptosis, and acquired resistance responses in several ALK ‐rearranged NSCLC cell lines and mouse xenograft tumor models and compared its efficacy to alectinib, a standard ALK inhibitor. Gilteritinib was significantly more potent than alectinib, as it inhibited cell proliferation at a lower dose, with complete attenuation of growth observed in several ALK ‐rearranged NSCLC cell lines and no development of drug tolerance. Immunoblotting showed that gilteritinib strongly suppressed phosphorylated ALK and its downstream effectors, as well as mesenchymal–epithelial transition factor (MET) signaling. By comparison, MET signaling was enhanced in alectinib‐treated cells. Furthermore, gilteritinib was found to more effectively abolish growth of ALK ‐rearranged NSCLC xenograft tumors, many of which completely receded. Interleukin‐15 (IL‐15) mRNA levels were elevated in gilteritinib‐treated cells, together with a concomitant increase in the infiltration of tumors by natural killer (NK) cells, as assessed by immunohistochemistry. This suggests that IL‐15 production along with NK cell infiltration may constitute components of the gilteritinib‐mediated antitumor responses in ALK ‐rearranged NSCLCs. In conclusion, gilteritinib demonstrated significantly improved antitumor efficacy compared with alectinib against ALK ‐rearranged NSCLC cells, which can warrant its candidacy for use in anticancer regimens, after further examination in clinical trial settings.
Type of Medium:
Online Resource
ISSN:
1347-9032
,
1349-7006
Language:
English
Publisher:
Wiley
Publication Date:
2023
detail.hit.zdb_id:
2115647-5
detail.hit.zdb_id:
2111204-6
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