Escape from HER family tyrosine kinase inhibitor therapy by the kinase inactive HER3

By N. Sergina, Megan Rausch, Donghui Wang, Jimmy A. Blair, B. Hann, Kevan M. Shokat, M. Moasser. Nature, 2007

1,006 citations recorded by the source corpus.

Oncogenic tyrosine kinases have proved to be promising targets for the development of highly effective anticancer drugs. However, tyrosine kinase inhibitors (TKIs) against the human epidermal growth factor receptor (HER) family show only limited activity against HER2-driven breast cancers, despite effective inhibition of epidermal growth factor receptor (EGFR) and HER2 in vivo. The reasons for this are unclear. Signalling in trans is a key feature of this multimember family and the critically important phosphatidylinositol-3-OH kinase (PI(3)K)/Akt pathway is driven predominantly through transphosphorylation of the kinase-inactive HER3 (refs 9, 10). Here we show that HER3 and consequently PI(3)K/Akt signalling evade inhibition by current HER-family TKIs in vitro and in tumours in vivo. This is due to a compensatory shift in the HER3 phosphorylation–dephosphorylation equilibrium, driven by increased membrane HER3 expression driving the phosphorylation reaction and by reduced HER3 phosphatase activity impeding the dephosphorylation reaction. These compensatory changes are driven by Akt-mediated negative-feedback signalling. Although HER3 is not a direct target of TKIs, HER3 substrate resistance undermines their efficacy and has thus far gone undetected. The experimental abrogation of HER3 resistance by small interfering RNA knockdown restores potent pro-apoptotic activity to otherwise cytostatic HER TKIs, re-affirming the oncogene-addicted nature of HER2-driven tumours and the therapeutic promise of this oncoprotein target. However, because HER3 signalling is buffered against an incomplete inhibition of HER2 kinase, much more potent TKIs or combination strategies are required to silence oncogenic HER2 signalling effectively. The biologic marker with which to assess the efficacy of HER TKIs should be the transphosphorylation of HER3 rather than autophosphorylation.

Subfields: Genetics, Oncology, Radiology, Nuclear Medicine and Imaging

View Paper: https://www.semanticscholar.org/paper/9d297ffa273b1770fe0e42af632d964bd636701c

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Genetics

1. Ruth Nussinov

In Oncology

1. M. Moasser
2. J. Baselga
3. S. Swain
4. N. Hynes
5. Gwen Macdonald
6. M. Wieduwilt
7. M. Sliwkowski
8. H. Horlings

In Radiology, Nuclear Medicine and Imaging

1. J. Baselga
2. M. Moasser
3. N. Hynes
4. S. Swain
5. Gwen Macdonald
6. M. Sliwkowski
7. Ruth Nussinov
8. H. Horlings

Citations in the corpus

• ErbB receptors and signaling pathways in cancer. (2009, background): “However, sustained ErbB3 inhibition was not observed with these TKIs, and PI3K activity was upregulated promoting tumor cell survival [43 ].”
• Improved classification of breast cancer by analysis of genetic alterations and gene expression profiling (2011, background): “…unclear why almost half of the breast cancer patients that overexpress HER2 are initially nonresponsive to trastuzumab-based therapy even when combined with chemotherapy or eventually become resistant to trastuzumab during treatment (Cobleigh et al., 1999; Slamon et al., 2001; Vogel et al., 2002).”
• Targeting the phosphoinositide 3-kinase (PI3K) pathway in cancer (2009, background): “Other known resistance mechanisms include the activation of alternative pathways, such as the induced gefitinib resistance through reactivation of HER3 signalling in lung cancer as a result of incomplete HER2 inhibition or amplification of hepatocyte growth factor receptor (also known as MET”
• Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. (2009, background): “Sergina et al. (2007) recently reported a compensatory feedback from PI3K inhibition that results in elevated pHER3.”
• The epidermal growth factor receptor family: Biology driving targeted therapeutics (2008, background): “This appears to be due to the failure of TKIs to effectively suppress ErbB3 signaling in these tumors due to Akt-driven negative feedback signaling loops [47].”
• Systematic prediction of drug combinations based on clinical side-effects (2014, background): “We further identified a condensed sub-network, highly inter-connected regions in the network (Figure 6B) with Cytoscape 27 and its plugin MCODE 28 The connections between the hub drugs include familiar drug combinations with similar mechanism of actions like hydrocortisone and dexamethasone (immunos”
• Novel anticancer targets: revisiting ERBB2 and discovering ERBB3 (2009, background): “These mechanisms might explain the modest activity of such agents in the clinic against breast cancers in which tumorigenesis is driven by ERBB2 (Ref”
• AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity (2011, neutral): “TORC1 inhibition by rapamycin has also been shown to activate signaling, and less-selective PI3K inhibitors that target both mTORC1 and PI3K have been shown to induce HER3 expression (Amin et al., 2010; Sergina et al., 2007).”
• Structure and dynamics of molecular networks: A novel paradigm of drug discovery: A comprehensive review (2012, background): “Targeting proteins in negative feedback loops may suppress the inhibitory effect of the feedback loop, and thereby activate the targeted pathway (Sergina et al., 2007).”