Negative regulation of TSC2 by exogenous cyclin D/CDK4/6 has been reported [13], and CDK4 or cyclin D1 knockdown led to a modest suppression of mTOR signaling in HER2+ breast cancer cells [9], effects which may contribute to the observed subtle reduction in S6 phosphorylation following long-term treatment with palbociclib (Supplementary Figure 1F) or CDK4/6 knockdown (Figure 1D). Here, CDK4 is linked to breast cancer.