Functional analysis of lung cancers with RASA1 mutations

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K08674
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Human pathology
• Research Institution: Juntendo University
• Principal Investigator: Hayashi Takuo 順天堂大学, 医学部, 准教授 (70569128)
• Co-Investigator(Kenkyū-buntansha): 齋藤 剛 順天堂大学, 医学部, 准教授 (80439736)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 肺癌

Outline of Final Research Achievements

Knockdown of RASA1 in HBECs activated signaling downstream of RAS and promoted cell growth. Conversely, restoration of RASA1 expression in RASA1-mutated cells reduced MAPK and PI3K signaling. While growth of cell lines with inactivation of only one of these two RasGAPs showed moderate and variable sensitivity to inhibitors of MEK or PI3K, cells with concurrent RASA1/NF1 mutations were profoundly more sensitive (IC50: 0.040u;M GSK1120212).
To better understand the histopathological features of these tumor, we compared histological features of 613 surgically resected lung adenocarcinomas in never or light smokers between each mitogenetic driver alteration. 79% of cases in our archive had mitogenic driver alterations; METex14 was the sixth most frequently altered gene (13 tumors, 2.1%), and other alterations included mutations of EGFR (59%), KRAS (6.0%), ERBB2 (2.5%), BRAF (2.5%), MAP2K1 (1.1%), fusions of ALK (2.6%), RET (1.0%), ROS1 (1.4%), and NRG1 (0.5%)。

Free Research Field

分子病理学、人体病理学

Academic Significance and Societal Importance of the Research Achievements

RASA1/NF1遺伝子変異陽性細胞はMEK阻害薬であるGSK1120212により、増殖が抑制されることが明らかとなり、GSK1120201がRASA1/NF1遺伝子変異陽性症例に対して新規治療薬となる可能性を示した。一方、TCGAのデータセットでは、RASA1の遺伝子変異は2.2%と報告されており、本件研究のコホートにおいても10～30症例程度RASA1遺伝子変異を有する症例を同定できると仮定していたが、非喫煙者・軽喫煙者ではRASA1遺伝子変異陽性の患者は同定されなかった。KRAS遺伝子変異と同様に人種間で変異率に差異がある可能性が示唆された。