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

Abstract

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.

Inactivation of Ymr1, Sjl2/3 phosphatases promotes stress resistance and longevity in wild type and Ras2G19V yeast

“…It is therefore interesting to speculate that increased autophagy may be involved in the reversal of Ras2G19Vp phenotype. This speculation is supported by the observation that substances like erianin and alisertib inhibit invasion and epithelial-mesenchymal transition of colorectal cancer cells carrying KRASG13D by a mechanism involving increased autophagy [ 34 , 35 ].…”

COL5A2-Dependent Cancer-associated Fibroblasts (CAF) Reveals Regulation of the Tumor Microenvironment and Response to Immunotherapy in Lung Adenocarcinoma

“…These results suggest that cytotoxic drug could kill both tumor cells and CAFs to destroy extracellular matrix and increase its permeability. Alisertib is reported exhibiting various regulatory effects on the PI3K/Akt and mitogen-activated protein kinase (MAPK) pathways [44]. In addition, AT13148 is a first-in-class multi-AGC kinase inhibitor.…”