The CDK4/6 inhibitor Palbociclib and the mTOR inhibitor MLN0128 are effective for the treatment of experimental intrahepatic cholangiocarcinoma

Question:

Intrahepatic cholangiocarcinoma (ICC) is an aggressive cancer lacking effective therapies and is associated with highly dismal prognosis. Palbociclib is a pan CDK4/6 inhibitor that has been shown to inhibit cell proliferation in many experimental cancer models. Our recent studies demonstrate that mTOR inhibitors, such as MLN0128, induce ICC cell apoptosis, but possess limited efficacy in inhibiting cell proliferation. As ICC cells are known to be highly proliferative, we hypothesized that Palbociclib might synergize with MLN0128 to induce ICC regression.

Methods:

Thus, we tested the therapeutic efficacy of Palbociclib, either alone or in combination, with MLN0128 in human ICC cell lines as well as in the AKT/YapS127A ICC mouse model.

Results:

We found that in vitro Palbociclib inhibits ICC cell growth via inhibiting cell cycle progression. The long-term cell growth, but not the short-term cell survival to Palbociclib is RB-dependent. Strikingly, concomitant administration of Palbociclib and MLN0128 revealed a strong, synergistic effect in inhibiting ICC cell growth. In the AKT/YapS127A ICC preclinical model, treatment of Palbociclib or MLN0128 alone all led to restrained tumor growth. Of note, combined treatment of Palbociclib with MLN0128 resulted in significant tumor regression in these mice.

Conclusion:

In conclusion, the combination therapy of CDK4/6 inhibitors with mTOR inhibitors might represent a novel, promising, and effective therapeutic approach against ICC.