Fig. 1

Simplified schematic diagram of the pathways described in this study. a Growth factor signalling (IGFR and ERBB) leads to activation of PI3K and phosphorylation of AKT. AKT inhibits TCS1/2, resulting in upregulation of mTORC1. In parallel, mTORC1 can also be upregulated by the RAS-RAF-MEK-ERK signalling pathway. ERK phosphorylates and inactivates TCS2 also leading to mTORC1 activation. S6 K1 activity increases as a result of mTORC1 activation. S6 K1 suppresses mTORC2 and IRS1. ER is also a target of S6 K1 leading to phosphorylation of serine 167. b Inhibition of mTORC1 with everolimus suppresses S6 K1 removing the negative feedback loop causing a rise in IRS1 and AKT activity via loss of suppression on mTORC2. Increased AKT activity suppresses TCS1/2 and increases expression of growth factor receptors (ERBB2/3) enhancing RAS-RAF-ERK signalling. c The dual blockade of ERBBs (neratinib) and mTORC1 signalling (everolimus) may suppress the two feedback loops described in b. Yellow shows normal mTORC signalling cascade; blue represents activated proteins; red represents inhibited proteins; dotted lines show loss of normal feedback loops