Activation of Src signaling mediates acquired resistance to ALK inhibition in lung cancer
別タイトル
ALK融合遺伝子陽性肺癌におけるALK阻害薬の耐性機序としてのSrcシグナル活性化の役割
著者
吉田, 遼平
(Yoshida, Ryohei)
上位タイトル
International journal of oncology
Vol.51,
No.5
(2017.
11)
,p.1533-
1540
識別番号
ISSN
1019-6439
DOI
10.3892/ijo.2017.4140.
その他
PMID:29048652
博士論文情報
学位授与番号
10107A521
学位授与年月日
2017-12-26
学位名
博士（医学）
学位授与機関
旭川医科大学
抄録
Anaplastic lymphoma kinase (ALK) fusion oncogenes occur in approximately 3-5% of non-small cell lung cancer (NSCLC) cases. Various ALK inhibitors are in clinical use for the treatment of ALK-NSCLC, including the first generation ALK inhibitor, crizotinib, and recently the more highly potent alectinib and ceritinib. However, most tumors eventually become resistant to ALK specific inhibitors. To address the mechanisms underlying the development of ALK inhibitor resistance, we used iTRAQ quantitative mass spectrometry and phosphor-receptor tyrosine kinase arrays to investigate intracellular signaling alterations in ALK inhibitor resistant NSCLC cell lines. Src signaling was identified as an alectinib resistance mechanism, and combination treatment with ALK and Src inhibitors was highly effective for inhibiting the growth of ALK inhibitor resistant cells in vitro and in mouse xenograft models. Furthermore, phospho-receptor tyrosine kinase activation and downstream PI3K/AKT signaling was effectively blocked by inhibiting Src in alectinib resistant cells. Finally, we showed that the combined use of ALK and Src inhibitors inhibited the growth of other ALK-NSCLC cell lines, including those that were ceritinib or lorlatinib resistant. Our data suggest that targeting Src signaling may be an effective approach to the treatment of ALK-NSCLC with acquired resistance to ALK inhibitors.
