The PI3K inhibitor copanlisib synergizes with sorafenib to induce cell death in hepatocellular carcinoma (HCC)

Purpose:

Sorafenib is a systemic treatment with established clinical benefit for patients with hepatocellular carcinoma (HCC) in advanced-stage disease; however chemoresistance and eventually disease progression occur almost invariably during treatment. Since activation of the PI3K/AKT pathway is thought to contribute to determine resistance to sorafenib, we evaluated in vitro the effects of combined treatment with sorafenib and copanlisib, an AKT inhibitor recently approved for clinical employment.

Design:

The antineoplastic effects of copanlisib alone and in combination with sorafenib were assessed in several HCC cell lines and in resistant cells obtained after long-term incubation with sorafenib by proliferation assays, colony formation, FACS analyses, and western blot.

Results:

Copanlisib strongly reduced cell viability and colony formation in different native and sorafenib-resistant HCC cell lines by affecting cyclin D1/CDK4/6/Rb signaling and causing cell cycle arrest. Copanlisib also counteracted sorafenib-induced phosphorylation of p-AKT and synergistically potentiated its antineoplastic effect.

Conclusions:

Copanlisib shows potent single agent anticancer activity and acts synergistically in combination with sorafenib in human HCC. Combination of sorafenib with copanlisib represents a rational therapeutic option for advanced HCC.