Oncogenic tyrosine kinases have proven to be promising targets for the development of highly effective anticancer drugs. However HER family tyrosine kinase inhibitors (TKIs) show only limited activity against HER2-driven cancers despite effective inhibition of EGFR and HER2 in vivo 1–8. The reasons for this are unclear. Signaling in trans is a key feature of this multimember family and the critically important PI3K/Akt pathway is driven predominantly through transphosphorylation of the kinase-inactive HER3 9,10. We report that HER3 and consequently PI3K/Akt signaling evade inhibition by current HER family TKIs in vitro and in tumors in vivo. This is due to a compensatory shift in HER3 phosphorylation-dephosphorylation equilibrium driven by increased membrane HER3 expression driving the phosphorylation reaction and reduced HER3 phosphatase activity impeding the dephosphorylation reaction. These compensatory changes are driven by Akt mediated negative feedback signaling. Although HER3 is not a direct target of TKIs, HER3 substrate resistance undermines their efficacy and has thus far gone undetected. The experimental abbrogation of HER3 resistance by siRNA knockdown restores potent pro-apoptotic effects to otherwise cytostatic HER TKIs, re-affirming the oncogene-addicted nature of HER2-driven tumors and the therapeutic promise of this oncoprotein target. However, since HER3 signaling is buffered against an incomplete inhibition of HER2 kinase, much more potent TKIs or combination strategies are required to effectively silence oncogenic HER2 signaling. The biologic marker to guide HER TKIs should be the transphosphorylation of HER3.

TGFbeta ligands act as tumor suppressors in early stage tumors but are paradoxically diverted into potent prometastatic factors in advanced cancers. The molecular nature of this switch remains enigmatic. Here, we show that TGFbeta-dependent cell migration, invasion and metastasis are empowered by mutant-p53 and opposed by p63. Mechanistically, TGFbeta acts in concert with oncogenic Ras and mutant-p53 to induce the assembly of a mutant-p53/p63 protein complex in which Smads serve as essential platforms. Within this ternary complex, p63 functions are antagonized. Downstream of p63, we identified two candidate metastasis suppressor genes associated with metastasis risk in a large cohort of breast cancer patients. Thus, two common oncogenic lesions, mutant-p53 and Ras, selected in early neoplasms to promote growth and survival, also prefigure a cellular set-up with particular metastasis proclivity by TGFbeta-dependent inhibition of p63 function.

Phosphorylation of the α-subunit of initiation factor 2 (eIF2) controls protein synthesis by a conserved mechanism. In metazoa, distinct stress conditions activate different eIF2α kinases (PERK, PKR, GCN2, and HRI) that converge on phosphorylating a unique serine in eIF2α. This collection of signaling pathways is termed the ‘integrated stress response’ (ISR). eIF2α phosphorylation diminishes protein synthesis, while allowing preferential translation of some mRNAs. Starting with a cell-based screen for inhibitors of PERK signaling, we identified a small molecule, named ISRIB, that potently (IC50 = 5 nM) reverses the effects of eIF2α phosphorylation. ISRIB reduces the viability of cells subjected to PERK-activation by chronic endoplasmic reticulum stress. eIF2α phosphorylation is implicated in memory consolidation. Remarkably, ISRIB-treated mice display significant enhancement in spatial and fear-associated learning. Thus, memory consolidation is inherently limited by the ISR, and ISRIB releases this brake. As such, ISRIB promises to contribute to our understanding and treatment of cognitive disorders.DOI: http://dx.doi.org/10.7554/eLife.00498.001