A novel therapeutic strategy targeting SFK for overcoming osimertinib resistance in lung cancer

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K07222
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47060:Clinical pharmacy-related
• Research Institution: Kyushu University
• Principal Investigator: Murakami Yuichi 九州大学, 薬学研究院, 共同研究員 (60464385)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: EGFR-TKI / SRC / 薬剤耐性 / オシメルチニブ

Outline of Final Research Achievements

Osimertinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that is developed against EGFR T790M resistance mutation. However, the appearance of tumors resistant to osimertinib has been reported. In this study, osimertinib-resistant non-small cell lung cancer cell lines (OR1 and OR2) which were established from NCI-H1975 cells showed SRC family kinase (SFK), AXL and CUB domain containing protein 1 (CDCP1). Silencing of AXL or CDCP1 induced inhibition of cell proliferation and phosphorylation of SFK and AKT in OR cells. In recurrent lung tumors after treatment with osimertinib, the expression of AXL and CDCP1 was markedly elevated as compared to pretreatments. Increased co-expression of AXL and CDCP1 is thus likely to confer cancer cells resistance to osimertinib, together with SRC co-activation. Taken together, our findings suggest that AXL, CDCP1 and SRC could be effective targets to overcome osimertinib resistance.

Free Research Field

腫瘍生物学

Academic Significance and Societal Importance of the Research Achievements

オシメルチニブは非小細胞肺癌に対する有効な治療薬であるが、オシメルチニブ耐性癌に対する耐性克服治療の開発が大きな課題である。本研究で、オシメルチニブ耐性肺癌細胞及びオシメルチニブ治療再発患者検体を用いた検討により、AXL、CDCP1がSRCを活性化しオシメルチニブ耐性に関与することを明らかにした。AXL、CDCP1及びSRCファミリーのオシメルチニブ耐性克服治療標的としての可能性を示すことができたことから、今後、オシメルチニブ治療患者の耐性克服治療の創出や適正化治療にも大きく貢献できると期待している。