演題抄録

臓器別シンポジウム

開催概要
開催回
第53回・2015年・京都
 

融合遺伝子陽性肺がんにおける分子標的薬耐性の分子基盤

演題番号 : OS4-1

[筆頭演者]
片山 量平:1 

1:公益財団法人がん研究会がん化学療法センター基礎研究部

 

During the last decade, the therapeutic strategies for the advanced non-small cell lung cancer (NSCLC) have been largely changed by the identification of various driver oncogenes, such as EGFR active mutation, ALK or ROS1 rearrangements, and the development of molecular targeted drugs. The molecular targeted drugs often induce market tumor shrinkage, however tumors relapse due to the development of resistant tumor. ALK or ROS1 gene rearrangement in NSCLC was first identified in 2007. For the treatment of ALK-rearranged NSCLC, currently ALK tyrosine kinase inhibitors (TKIs) crizotinib, alectinib (in Japan) and ceritinib (in US and EU) are clinically available, and multiple next-generation ALK-TKIs are under clinical evaluation. For the ROS1-rearrnaged NSCLC, various TKIs including crizotinib are under clinical evaluation. ALK- or ROS1-rearranged tumors show market response to the TKIs, however, cancers inevitably develop resistance to TKIs by the various mechanisms. To identify how cancers develop resistance to the TKIs, we have established multiple cell line models of acquired resistance to the ALK/ROS1-TKIs using EML4-ALK or CD74-ROS1 expressing Ba/F3 cells or H3122 cells (harboring EML4-ALK), and the cancer cell lines established from the patient relapsed on ALK-TKIs under IRB approved protocol. As the results, various mutations in ALK or ROS1 or bypass pathway activation mediated TKI resistance have been identified. To overcome the resistance, we examined the sensitivity of structurally distinct ALK- or ROS1-TKIs to each resistance mutations. We also tested combination of the ALK-TKIs with TKIs targeting the receptor tyrosine kinase which contributes to ALK-TKI resistance. Our study suggested that each ALK- or ROS1-TKIs have different potency to each resistance mutants, and the most suitable ALK- or ROS1-TKI or combination therapy would be required for the treatment of the resistant tumor based on the resistant mechanisms in each patient.

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