Abstract 6493: CRISPR-directed prime editing sensitizes EGFR inhibitor by correcting oncogenic KRAS mutants In NSCLC

Abstract

Abstract EGFR inhibitor has been demonstrated with huge therapeutic potential in advanced non-small cell lung cancer (NSCLC), while the patients carrying KRAS mutation had poor response to EGFR inhibitor. KRAS mutation is the most frequent molecular alteration found in advanced NSCLC, which is associated with a poor prognosis without available targeted therapy. Previous research showed that CRISPR-directed prime editor could induce unconstrained correction for KRAS mutants (KRASG12D, KRASG12C, KRASG12V). Accordingly, it would be a promising strategy to combine PE-based genetic therapy with EGFR inhibitor for enhanced therapy in NSCLC. Here,we selected several PE variants with reported highly efficient reverse transcriptase, among which eEc48-based PE6a showed the highest editing efficiency toward KRAS mutation. The lentivirus-mediated PE6a editing inhibited cell proliferation and invasion in vitro and in vivo. After that, EGFR inhibitor combined with PE6a was employed in patient-derived organoid (PDO) model carrying diverse KRAS mutants. We found that PE6a editing significantly inhibited PDO proliferation compared to EGFR inhibitor alone and control. Correspondingly, the transcriptome sequencing also showed that the cell apoptosis, cell growth and cell motility signaling were inhibited upon PE6a editing. Our findings demonstrated that the PE-directed genetic therapy could sensitize EGFR inhibitor in NSCLC, providing an alternative choice for NSCLC patients carrying KRAS mutant. Citation Format: Qingxiao Fang, Chao Yang, Chongbiao Huang, Hongwei Wang, Jun Yu, Jihui Hao. CRISPR-directed prime editing sensitizes EGFR inhibitor by correcting oncogenic KRAS mutants In NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6493.