Functional analysis of coexisting RBM10 mutations in EGFR-mutated lung cancer

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K15546
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Kanazawa University
• Principal Investigator: Nanjo Shigeki 金沢大学, 附属病院, 講師 (00722555)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 分子標的薬耐性 / RBM10遺伝子変異 / EGFR変異肺癌 / スプライシング因子

Outline of Final Research Achievements

In EGFR lung cancer patients, RBM10 mutation as a co-mutation occurred in 7.6% of patients in addition to oncogene EGFR mutation, and knockout of RBM10 attenuated apoptosis induced by EGFR inhibitors. We also found that PFS and response rate to EGFR inhibitors were significantly lower in patients with coexisting RBM10 mutations. In addition, the ratio of apoptosis-promoting factor Bcl-xS to apoptosis-resisting factor Bcl-xL was decreased by RBM10 deficiency. Then, we showed that the combination of a Bcl-xL inhibitor with an EGFR inhibitor can overcome this intrinsic resistance.

Free Research Field

呼吸器内科学

Academic Significance and Societal Importance of the Research Achievements

第3世代のEGFRチロシンキナーゼ阻害薬 (EGFR-TKI) であるOsimertinibは、EGFR遺伝子変異陽性肺癌 (EGFR肺癌)に対してよく奏効し、高い有効性を示す。しかしながら、当初から腫瘍が縮小しない、初期耐性も2-3割に認め、この原因解明と耐性克服が重要な課題であるが、申請者は本研究においてその機序と克服法を示した。
本研究において、肺癌の分子標的薬耐性の新たなメカニズムが同定されるとともに、治療法の候補が見つかったことから、近い将来耐性克服を目指す臨床試験が行われ、成果が患者に還元される可能性が生まれた。