Synergistic Effects of the Combination of Alpelisib (PI3K Inhibitor) and Ribociclib (CDK4/6 Inhibitor) in Preclinical Colorectal Cancer Models

The CDK4/6 inhibitor Ribociclib has shown limited efficacy as a monotherapy in colorectal cancer (CRC). However, combining Ribociclib with targeted therapies could present a viable strategy for treating CRC. This study evaluated the combination of Ribociclib and the PI3K inhibitor Alpelisib across four distinct cell lines representing different mutational statuses (<i>PIK3CA/KRAS</i> wild-type, <i>KRAS</i>-mutated, <i>PIK3CA</i>-mutated, and <i>PIK3CA/KRAS</i>-mutated). We analyzed the drugs' impact on key proteins involved in the PI3K pathway, cell cycle regulation, and apoptosis. The combination of Alpelisib and Ribociclib demonstrated a synergistic anti-proliferative effect across all cell lines, leading to a simultaneous decrease in pRB, pAKT, and p-S6 levels, and a more comprehensive suppression of the PI3K/AKT/mTOR pathway. Additionally, there was an upregulation of the apoptotic marker, p-BCL2, in cells treated with the combination compared to controls. In vivo studies using Caco-2, LS1034, and SNUC4 xenografts revealed a significant reduction in tumour growth with the combination therapy compared to single-agent treatments. These findings suggest that combining Alpelisib and Ribociclib could be a promising therapeutic approach for CRC, warranting further clinical exploration.