Combined CDK4/6 and Pan-mTOR Inhibition Is Synergistic Against Intrahepatic Cholangiocarcinoma

Abstract

Intrahepatic cholangiocarcinoma (ICC) is an aggressive cancer type, lacking effective therapies and associated with a dismal prognosis. Palbociclib is a selective CDK4/6 inhibitor, which has been shown to suppress cell proliferation in many experimental cancer models. Recently, we demonstrated that pan-mTOR inhibitors, such as MLN0128, effectively induce apoptosis, although have limited efficacy in restraining proliferation of ICC cells. Here, we tested the hypothesis that palbociclib, due to its antproliferative properties in many cancer types, might synergize with MLN0128 to impair ICC growth. Human ICC cell lines and the AKT/YapS127A ICC mouse model were used to test the therapeutic efficacy of palbociclib and MLN0128, either alone or in combination. Administration of palbociclib suppressed ICC cell growth by inhibiting cell-cycle progression. Concomitant administration of palbociclib and MLN0128 led to a pronounced, synergistic growth constraint of ICC cell lines. Furthermore, while treatment with palbociclib or MLN0128 alone resulted in tumor growth reduction in AKT/YapS127A mice, a remarkable tumor regression was achieved when the two drugs were administered simultaneously. Mechanistically, palbociclib was found to potentiate MLN0128 mTOR inhibition activity, whereas MLN0128 prevented the upregulation of cyclin D1 induced by palbociclib treatment. Our study indicates the synergistic activity of palbociclib and MLN0128 in inhibiting ICC cell proliferation. Thus, combination of CDK4/6 and mTOR inhibitors might represent a novel, promising, and effective therapeutic approach against human ICC.

Cyclin‐dependent kinase 4 inhibits the translational repressor 4E‐BP1 to promote cap‐dependent translation during mitosis–G1 transition

“…These findings shed further light on the cell cycle-dependent phosphorylation of 4E-BP1, the regulation of which was previously reported to be mediated by CDK1 and CDK12 in mitotic cells [29,61,62], and PLK1 and CDK1 in cells undergoing meiosis [22,32,[63][64][65]. Given this newly discovered role of CDK4, it is likely that inhibition of mitotic 4E-BP1 phosphorylation is a previously unknown function of CDK4/6 inhibitors such as palbociclib, and may explain the synergy between these drugs and mTOR inhibitors [66][67][68][69][70][71][72]. It is important to try to reconcile these observations with those previously observed that report CDK1 as the principal kinase that phosphorylates 4E-BP1 during mitosis [30,33].…”

GSG2 knockdown suppresses cholangiocarcinoma progression by regulating cell proliferation, apoptosis and migration

“…Previous studies have revealed that PI3K/AKT, CCND1/CDK6 and MAPK pathways play key role in developing CCA [37][38][39][40]. For example, Wang et al, clari ed that TSPAN1 was involved in CCA progression via PI3K/AKT pathway [41].…”

Role of Glucose Metabolism Reprogramming in the Pathogenesis of Cholangiocarcinoma

“…The mTOR pathway regulates energy homeostasis and engages in cancer cell survival in cellular metabolic stress such as depletion in nutrients and energy (23,24). The downregulation of mTOR pathway signaling reduces cancer growth and has therapeutic potential for CCA (61)(62)(63)(64). CCA cells which need OXPHOS for energy requirements can be targeted by impairing mitochondrial energy metabolism.…”