Trametinib overcomes KRAS‐G12V–induced osimertinib resistance in a leptomeningeal carcinomatosis model of EGFR‐mutant lung cancer. Issue 9 (22nd July 2021)

• Record Type: Journal Article
• Authors: Fukuda, Koji; Otani, Sakiko; Takeuchi, Shinji; Arai, Sachiko; Nanjo, Shigeki; Tanimoto, Azusa; Nishiyama, Akihiro; Naoki, Katsuhiko; Yano, Seiji
• Is Part Of: Cancer science. Volume 112:Issue 9(2021)
• Page Start: 3784
• Page End: 3795
• Publication Date: 2021-07-22
• Subjects: epidermal growth factor receptor -- leptomeningeal carcinomatosis -- non–small cell lung cancer -- osimertinib -- trametinib; Cancer -- Periodicals; Neoplasms -- Periodicals; Research -- Periodicals; Electronic journals; 616.994005
• DOI: 10.1111/cas.15035
• Languages: English
• ISSNs: 1347-9032

Abstract

Abstract: Leptomeningeal carcinomatosis (LMC) occurs frequently in non–small cell lung cancer (NSCLC) harboring epidermal growth factor receptor ( EGFR ) mutations and is associated with acquired resistance to EGFR tyrosine kinase inhibitors (EGFR‐TKIs). However, the mechanism by which LMC acquires resistance to osimertinib, a third‐generation EGFR‐TKI, is unclear. In this study, we elucidated the resistance mechanism and searched for a novel therapeutic strategy. We induced osimertinib resistance in a mouse model of LMC using an EGFR ‐mutant NSCLC cell line (PC9) via continuous oral osimertinib treatment and administration of established resistant cells and examined the resistance mechanism using next‐generation sequencing. We detected the Kirsten rat sarcoma ( KRAS )‐G12V mutation in resistant cells, which retained the EGFR exon 19 deletion. Experiments involving KRAS knockdown in resistant cells and KRAS ‐G12V overexpression in parental cells revealed the involvement of KRAS ‐G12V in osimertinib resistance. Cotreatment with trametinib (a MEK inhibitor) and osimertinib resensitized the cells to osimertinib. Furthermore, in the mouse model of LMC with resistant cells, combined osimertinib and trametinib treatment successfully controlled LMC progression. These findings suggest a potential novel therapy against KRAS ‐G12V–harboring osimertinib‐resistant LMC in EGFR ‐mutant NSCLC. Abstract : Kirsten rat sarcoma (KRAS)‐G12V mutation plays a key role in the development of osimertinib resistance in EGFR‐mutant non–small cell lung cancer (NSCLC). Leptomeningeal carcinomatosis progression can be controlled by combinatorial treatment with osimertinib and trametinib.