PI3K p110α Blockade Enhances Anti-Tumor Efficacy of Abemaciclib in Human Colorectal Cancer Cells

Abstract

Targeting cell cycle regulation in colorectal cancer has not been fully evaluated. We investigated the efficacy of the CDK4/6 inhibitor, abemaciclib, and confirmed a synergistic interaction for PI3K p110α and CDK dual inhibition in colorectal cancer cell lines. Caco-2 and SNU-C4 cell lines were selected to explore the mechanism of action for and resistance to abemaciclib. In vitro and in vivo models were used to validate the anti-tumor activity of abemaciclib monotherapy and BYL719 combination therapy. Abemaciclib monotherapy inhibited cell cycle progression and proliferation in Caco-2 and SNU-C4 cells. CDK2-mediated Rb phosphorylation and AKT phosphorylation appeared to be potential resistance mechanisms to abemaciclib monotherapy. Abemaciclib/BYL719 combination therapy demonstrated synergistic effects regardless of PIK3CA mutation status but showed greater efficacy in the PIK3CA mutated SNU-C4 cell line. Growth inhibition, cell cycle arrest, and migration inhibition were confirmed as mechanisms of action for this combination. In an SNU-C4 mouse xenograft model, abemaciclib/BYL719 combination resulted in tumor growth inhibition and apoptosis with tolerable toxicity. Dual blockade of PI3K p110α and CDK4/6 showed synergistic anti-tumor effects in vivo and in vitro in human colorectal cancer cell lines. This combination could be a promising candidate for the treatment of patients with advanced colorectal cancer.

Modulation of autophagy and apoptosis can contribute to the anticancer effect of Abemaciclib/Celecoxib combination in colon cancer cells

“…The influence of Abemaciclib on migration was assessed by a scratch wound healing assay, and it was found that Abemaciclib significantly inhibited cell migration in Caco-2 cells, consistent with the present findings [ 52 ]. Abemaciclib’s capacity to enhance active Rb protein levels and reduce NF-κB might be the cause of its anti-migratory effects.…”

Induction of Apoptosis via Inactivating PI3K/AKT Pathway in Colorectal Cancer Cells Using Aged Chinese Hakka Stir-Fried Green Tea Extract

“…As a downstream signal of PI3K/AKT, the progression of cell cycle is necessary for colon cancer proliferation. Several small-molecule inhibitors, such as botulin and periplocymarin, blocked cell-cycle progression in colon cancer cells by silencing PI3K/AKT signalling, accompanied by the expression of cycle-related proteins such as cyclin-dependent kinase (including CDK2, CDK4 and CDK6) and cyclins (Cyclin B1 or D1) [ 12 , 13 , 14 ]. In addition, the pharmacological inhibition of PI3K/AKT may promote colon cancer cell apoptosis by regulating apoptosis-related proteins such as PARP, Bcl2 and Bax, and show effective antitumor effects [ 12 , 15 ].…”

Induction of apoptosis via inactivating PI3K/AKT pathway in colorectal cancer cells with the aged Hakka stir-fried green tea

“…As a downstream signal of PI3K/AKT, the progression of cell cycle is necessary for colon cancer proliferation. Several small-molecule inhibitors, such as botulin or periplocymarin, blocked cell cycle progression in colon cancer cells by silencing PI3K/AKT signaling, accompanied by the expression of cycle-related proteins such as cyclin-dependent kinase (including CDK2, CDK4 or CDK6) and cyclins (Cyclin B1 or D1) [12][13][14]. In addition, the pharmacological inhibition of PI3K/AKT may promote colon cancer cell apoptosis by regulating apoptosis-related proteins PARP, Bcl2 and Bax, and show effective anti-tumor effects [12,15].…”