PIK75 effectively reverses PI3K‒AKT activation caused by palbociclib resistance and synergistically inhibits the progression of esophageal squamous cell carcinoma

China is one of the countries with a high incidence of esophageal squamous cell carcinoma (ESCC). At present, the main treatment method for ESCC is surgery combined with chemotherapy and radiotherapy, and the efficacy of drug therapy is not ideal. Cyclin-dependent kinase inhibitors (CDKi) have shown amazing efficacy in treating some types of cancer, especially breast cancer, but their therapeutic effects on ESCC are limited. In the present study, we found that the CDK inhibitor palbociclib could successfully arrest cells in the G0/G1 phase but did not inhibit the proliferation of some types of ESCC cells. Further experiments revealed that activation of the PI3K‒AKT pathway was key for palbociclib resistance. Therefore, we investigated the potential of combining palbociclib with the novel PI3K inhibitor PIK75 to inhibit the growth of ESCC cell lines and xenograft tumors. The combined use of palbociclib and PIK75 synergistically inhibited the expression of the cell cycle proteins CCNE1, CDC6, and CDC25A, as well as the abnormal activation of PIK3CA and AKT phosphorylation. The combination of these two drugs synergistically inhibited tumor cell cycle progression and promoted apoptosis in vitro and in vivo, which provides a promising idea for the treatment of ESCC in the future.