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posted on 2023-04-03, 15:22 authored by Chan Woo Kang, Kang Won Jang, Jinyoung Sohn, Sung-Moo Kim, Kyoung-Ho Pyo, Hwan Kim, Mi Ran Yun, Han Na Kang, Hye Ryun Kim, Sun Min Lim, Yong Wha Moon, Soonmyung Paik, Dae Joon Kim, Joo Hang Kim, Byoung Chul Cho <p>Supplementary Figure 3B and C. Inhibition of FAK activity in LC-2/ad cells and LC-2/ad DR cells B, Western blot analysis of indicated markers in LC-2/ad and LC-2/ad DR cells after treated with 1mM of dovitinib (DO), dasatinib (DA), saracatinib (SA), or PF562,271 (PF) for 4hr. C, Western blot analysis of indicated markers in LC-/2ad and LC-2/ad DR cells after treated with indicated dose of dovitinib (DO) for 4hr.</p>
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ARTICLE ABSTRACT
RET rearrangement is a newly identified oncogenic mutation in lung adenocarcinoma (LADC). Activity of dovitinib (TKI258), a potent inhibitor of FGFR, VEGFR, and PDGFR, in RET-rearranged LADC has not been reported. The aims of the study are to explore antitumor effects and mechanisms of acquired resistance of dovitinib in RET-rearranged LADC. Using structural modeling and in vitro analysis, we demonstrated that dovitinib induced cell-cycle arrest at G0–G1 phase and apoptosis by selective inhibition of RET kinase activity and ERK1/2 signaling in RET-rearranged LC-2/ad cells. Strong antitumor effect of dovitinib was observed in an LC-2/ad tumor xenograft model. To identify the acquired resistance mechanisms to dovitinib, LC-2/ad cells were exposed to increasing concentrations of dovitinib to generate LC-2/ad DR cells. Gene-set enrichment analysis of gene expression and phosphor-kinase revealed that Src, a central gene in focal adhesion, was activated in LC-2/ad DR cells. Saracatinib, an src kinase inhibitor, suppressed ERK1/2 phosphorylation and growth of LC-2/ad DR cells. Taken together, these findings suggest that dovitinib can be a potential therapeutic option for RET-rearranged LADC, in which acquired resistance to dovitinib can be overcome by targeting Src. Mol Cancer Ther; 14(10); 2238–48. ©2015 AACR.
