CDK4/6 inhibition suppresses mTOR activity and growth in lymphangioleiomyomatosis (LAM)

Dysregulation of the cyclin D1-CDK4/6-Rb axis and the PI3K/Akt/mTOR pathway are hallmark features of proliferative disorders, including lymphangioleiomyomatosis (LAM), a rare lung disease characterized by TSC1/2 loss and hyperactive mTORC1. We investigated repurposing of CDK4/6 inhibitors (CDK4/6i), agents approved for estrogen receptor-positive breast cancer, for treatment of LAM by targeting the crosstalk between cell cycle progression and mTORC1 signaling.

We investigated the impact of the CDK4/6i palbociclib on mTORC1 signaling in TSC2-null human-derived cells, TSC2-deficient mouse embryonic fibroblasts (MEFs), and cellular breast cancer models. Mechanisms of crosstalk of cell cycle and mTOR pathways, and effect of palbociclib on autophagic and cell death markers were assessed. Pre-clinical therapeutic efficacy was validated in vivo using a novel chick chorioallantoic membrane (CAM) xenograft model of LAM.

Palbociclib treatment robustly suppressed mTORC1 activity across multiple genetic backgrounds. In TSC2-deficient cells, CDK4/6 inhibition partially reduced phosphorylation of the mTORC1 targets. Notably, while mTORC1 inhibitor rapamycin induced pro-survival autophagy, the addition of palbociclib disrupted autophagic flux, facilitating a switch to apoptotic cell death. In vivo, palbociclib monotherapy significantly reduced TSC2-null tumor burden to a degree comparable to rapamycin.

These findings identify CDK4/6 as a critical regulator that not only suppresses hyperactive mTORC1 activity in different cellular contexts but also blocks pro-survival autophagy by converting a growth-suppressive response into apoptotic cell death. This research provides a mechanistic rationale for further investigation of CDK4/6 inhibitors. These findings offer a potential strategy for alternative or combination treatments in patients with lymphangioleiomyomatosis.