Abstract 287: A novel class III receptor tyrosine kinase inhibitor synergizes with olaparib by inhibition of DNA repair-related genes in non-small cell lung cancer cells

Abstract

Abstract The platelet-derived growth factor receptors (PDGFRs), which are classified with class III receptor tyrosine kinase (RTK) family, play critical roles in cell proliferation, differentiation, and malignancy in various types of human cancers. To develop novel class III RTK inhibitors, dozen novel oxazole amine derivatives were designed and synthesized. Among the synthesized compounds, KM201 showed inhibitory activities of pan-class III RTK by an in vitro kinase activity assay and potent anti-proliferative activities in variety of cancer cell lines including leukemia and solid cancer cells. Genome-wide RNAseq profiling revealed a significant decrease of DNA repair-related genes in non-small cell lung cancer A549 cells treated with KM201. Moreover, KM201-induced DNA damage was detected by H2AX phosphorylation, which led to cell cycle arrest in the G2/M phase. We hypothesized that KM201 in combination with a PARP inhibitor may exhibit synergistic effect on inhibition of proliferation since PARP inhibitors are primarily effective against cancers with loss-of-function mutations in BRCA1 and BRCA2. Combination of KM201 and olaparib (a PARP inhibitor) markedly more effective in anti-proliferation and apoptotic cell death in A549 and H1299 cells harboring wild type BRCA1/2, compared with either drug alone. Our results show that the novel class III RTK inhibitor KM201 inhibits proliferation of leukemia and solid tumor cells by potentiating DNA damage and exerts synergistic cytotoxicity in combination with olaparib. Further detailed studies could help to investigate the full potential of KM201 as a class III RTK inhibitor and a combination adjuvant of PARP inhibitors. Citation Format: Hwani Ryu, Jie-young Song, Sang-Gu Hwang, Jiyeon Ahn. A novel class III receptor tyrosine kinase inhibitor synergizes with olaparib by inhibition of DNA repair-related genes in non-small cell lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 287.