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

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

doi:10.3892/etm.2023.11942

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

Exp Ther Med. 2023 Apr 11;25(6):243. doi: 10.3892/etm.2023.11942. eCollection 2023 Jun.

Authors

Baojun Ren¹, Yan Geng¹, Shuxiang Chen², Zhuowei Gao¹, Kehong Zheng³, Yong Yang⁴, Qimei Luo⁵, Jing Feng¹, Zhentao Luo¹, Yongle Ju¹, Zonghai Huang³

Affiliations

¹ Department of Gastrointestinal Surgery, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), The Second School of Clinical Medicine, Southern Medical University, Foshan, Guangdong 528308, P.R. China.
² Department of Anesthesiology and Operating Theatre, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), The Second School of Clinical Medicine, Southern Medical University, Foshan, Guangdong 528308, P.R. China.
³ Department of General Surgery, Zhujiang Hospital, Southern Medical University, The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China.
⁴ Department of Gastrointestinal Surgery, Peking University Shougang Hospital, Beijing 100144, P.R. China.
⁵ Department of Nephrology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), The Second School of Clinical Medicine, Southern Medical University, Foshan, Guangdong 528308, P.R. China.

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.

Keywords: MAPK pathway; PI3K/Akt pathway; RAS; alisertib; apoptosis; autophagy; colorectal cancer.

Grants and funding

Funding: The present study was funded by the Medical Science and Technology Research Project of Foshan City (grant. nos. 2017AB003533, 2220001004234, 2020001005635), the Medical Science and Technology Research Foundation of Guangdong Province (grant. no. A2018150), the Scientific Research Start Plan of Shunde Hospital, Southern Medical University (grant. no. SRSP2018002), the Medical Science and Technology Research Project of Foshan City (grant. nos. 2220001004234 and 2020001005635) and the Foshan Medical Key Talent Project.