1. Volume 29, Issue 3, Pages 243-244 (March 2016)
CDK4/6 Inhibitors resTORe Therapeutic Sensitivity in HER2+ Breast Cancer 
Marcos Malumbres 
Cancer Cell 
Volume 29, Issue 3, Pages (March 2016)
DOI: /j.ccell
Copyright © 2016 Elsevier Inc. Terms and Conditions

2. Figure 1
Crosstalk between the HER2-mTOR and Cyclin D1-CDK4/6 Pathways Suggests New Combination Therapies in HER2-Positive Breast Cancer
EGFR and HER2 belong to a family of receptor tyrosine kinases frequently hyperactivated in cancer, leading to constitutive signaling through AKT and mTOR (a component of the mTORC1 complex). This pathway triggers cell progression by inducing the expression of cyclin D1, which in turn activates CDK4/6, leading to phosphorylation (P) and inactivation of the retinoblastoma protein (pRb). Cyclin D1-CDK4/6 can also participate in EGFR/HER2 signaling by inducing the phosphorylation and inactivation of TSC2, an mTORC1 inhibitor. Inhibition of CDK4/6 results in TSC2 activation and inhibition of the mTOR/p70-S6K pathway, relieving an inhibitory feedback loop that limits EGFR/HER2 signaling. As a consequence, cells treated with CDK4/6 inhibitors such as abemaciclib display enhanced EGFR/HER2 activity and increased sensitivity to EGFR/HER2 kinase inhibitors such as lapatinib or anti-HER2 antibodies such as trastuzumab, two drugs currently used to treat HER2-positive breast cancers. Other connections between these pathways are not indicated for simplicity. Kinases are in purple. Dashed lines indicate indirect or unknown connections between the indicated molecules.
Cancer Cell  , DOI: ( /j.ccell )
Copyright © 2016 Elsevier Inc. Terms and Conditions