Pharmacological SHIP2 blockade enhances sensitivity to standard and targeted cancer therapies

Abstract

Esophageal squamous cell carcinoma (eSCC) is an aggressive malignancy with poor prognosis and limited therapeutic options. The phosphoinositide 3-kinase (PI3K)/AKT pathway is frequently activated in eSCC, but clinical use of PI3K or AKT inhibitors is restricted by toxicity and compensatory signaling. SHIP2, an inositol 5-phosphatase encoded by INPPL1, modulates this pathway by converting PI(3,4,5)P₃ to PI(3,4)P₂, thereby regulating AKT activation. We previously identified INPPL1 amplification as recurrent in eSCC and demonstrated that SHIP2 inhibition suppresses tumor growth and synergizes with PLK1 inhibition.

Here, we extend these findings and show that SHIP2–PLK1 synergy is not confined to eSCC but is also observed in multiple colorectal cancer cell lines, revealing a conserved vulnerability across tumor types. Mechanistic analyses demonstrate that this synergy depends on PI3K/AKT signaling, with SHIP2 inhibition producing stronger effects than direct PI3K blockade, suggesting additional regulatory functions beyond canonical PI3K control. Furthermore, SHIP2 inhibition enhances the cytotoxic activity of standard chemotherapies, including 5-fluorouracil and paclitaxel, in eSCC cells. Importantly, these effects occur at sub-cytotoxic drug concentrations, indicating potential therapeutic benefit with reduced toxicity.

Collectively, our results identify SHIP2 as a central regulator of the PI3K/AKT axis in eSCC and colorectal cancer and highlight its value as a combinatorial target. SHIP2 inhibition represents a promising strategy to potentiate existing chemotherapies and targeted agents, opening new avenues for the treatment of refractory gastrointestinal cancers.