Alisertib exerts KRAS allele-specific anticancer effects on colorectal cancer cell lines

作者：Ren, Baojun; Geng, Yan; Chen, Shuxiang; Gao, Zhuowei; Zheng, Kehong; Yang, Yong; Luo, Qimei; Feng, Jing; Luo, Zhentao; Ju, Yongle^*; Huang, Zonghai^*

来源：Experimental and Therapeutic Medicine, 2023, 25(6): 243.

DOI：10.3892/etm.2023.11942

• colorectal cancer
• RAS
• PI3K
• Akt pathway
• MAPK pathway
• alisertib
• apoptosis
• autophagy

The aim of the present study was to examine the effects of alisertib (ALS) on RAS signaling pathways against a panel of colorectal cancer (CRC) cell lines and engineered Flp-In stable cell lines expressing different Kirsten rat sarcoma virus (KRAS) mutants. The viability of Caco-2(KRAS wild-type), Colo-678(KRAS G12D), SK-CO-1(KRAS G12V), HCT116(KRAS G13D), CCCL-18(KRAS A146T) and HT29(BRAF V600E) cells was examined by Cell Titer-Glo assay, and that of stable cell lines was monitored by IncuCyte. The expression levels of phosphorylated (p-)Akt and p-Erk as RAS signal outputs were measured by western blotting. The results suggested that ALS exhibited different inhibitory effects on cell viability and different regulatory effects on guanosine triphosphate (GTP)-bound RAS in CRC cell lines. ALS also exhibited various regulatory effects on the PI3K/Akt and mitogen-activated protein kinase (MAPK) pathways, the two dominant RAS signaling pathways, and induced apoptosis and autophagy in a RAS allele-specific manner. Combined treatment with ALS and selumetinib enhanced the regulatory effects of ALS on apoptosis and autophagy in CRC cell lines in a RAS allele-specific manner. Notably, combined treatment exhibited a synergistic inhibitory effect on cell proliferation in Flp-In stable cell lines. The results of the present study suggested that ALS differentially regulates RAS signaling pathways. The combined approach of ALS and a MEK inhibitor may represent a new therapeutic strategy for precision therapy for CRC in a KRAS allele-specific manner; however, this effect requires further study in vivo.

• 单位
  1; 北京大学; 南方医科大学