Drug resistance mechanisms and therapeutic strategies in rare driver oncogene positive cancers

2018 Fiscal Year Final Research Report

• Project/Area Number: 16H04715
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Tumor therapeutics
• Research Institution: Japanese Foundation for Cancer Research
• Principal Investigator: Katayama Ryohei 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, 部長 (60435542)
• Research Collaborator: SETO yosuke ; UCHIBORI ken ; NISHIO makoto ; YANAGITANI noriko ; TAKEUCHI kengo ; OH-HARA tomoko ; KOIKE sumie ; OKADA koutaroh ; SHIMIZU yuki
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: Driver Oncogene / 獲得耐性 / 耐性克服法

Outline of Final Research Achievements

In lung cancer, low frequency driver oncogenes such as ALK, ROS1, RET and NTRK fusion genes are targeted by the development of multiple tyrosine kinase inhibitors. These TKIs often shows marked tumor shrinkage for a couple years, however, the tumor inevitably relapses due to the emergence of acquired resistance. In the final year, we found and reported that 14 compound mutations in ALK kinase domain confers the resistance to most potent 3rd generation ALK inhibitor lorlatinib, but some of these resistance mutations became re-sensitive to 1st or 2nd generation ALK-TKIs. In addition, in ROS1 rearranged lung cancer, a couple of patient derived cell lines were newly established from the malignant pleural effusion, and evaluated a new inhibitor under collaboration. In addition, we clarified and published the relationship between the order of EGFR-TKIs use and the pattern of resistance mutation emergence.

Free Research Field

腫瘍治療学

Academic Significance and Societal Importance of the Research Achievements

低頻度ながらDriver Oncogene陽性肺がんに対しては高い腫瘍縮小効果を示す治療薬が、複数開発され臨床応用されてきたが、獲得耐性が大きな問題として立ちはだかる。本研究において、複数の新規耐性機構と克服法を明らかにしてきたが、中でも重複耐性変異による第3世代阻害薬耐性が再び第１，２世代阻害薬への感受性を取り戻すという発見は、今後の治療順番を考えたり、耐性時にそのメカニズムに合わせた最適な治療法選択の重要性を提起するインパクトの大きな発見といえる。