Resiliency and Vulnerability in the HER2-HER3 Tumorigenic Driver

Abstract

About 25% of breast cancers harbor the amplified oncogene HER2 and are dependent on HER2 kinase function, identifying HER2 as a vulnerable target for therapy. However,. HER2-HER3 activation is buffered so that it is protected against a nearly two log inhibition of HER2 catalytic activity; this buffering is driven by the negative regulation of HER3 by Akt. We have now further characterized HER2-HER3 signaling activity and shown that the compensatory buffering prevents apoptotic tumor cell death from occurring as a result of the combined loss of MAPK and Akt signaling. To overcome the cancer cells' compensatory mechanisms, we co-administered a PI3K/ mTor inhibitor and a HER2 tyrosinc kinase inhibitor. This treatment strategy proved suboptimal because it induced both tyrosine kinase inhibitor sensitizing and desensitizing effects and robust cross-compensation of MAPK and Akt signaling pathways. Noting that HER2-HER3 activity was completely inhibited by higher, fully inactivating doses of TKI, we then attempted to overcome the cells compensatory buffering with this higher dose. This treatment crippled all downstream signaling and induced tumor apoptosis. Although such high doses of TKI are toxic in vivo when given continuously, we found that intermittent doses of TKI administered to mice produced sequential cycles of tumor apoptosis and ultimately complete tumor regression in mouse models, with much less toxicity. This strategy for inactivation of HER2-HER3 tumorigenic activity is proposed for clinical testing.

Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors

“…5D). As shown previously, lapatinib induced HER3 mRNA (23). However, the effect of lapatinib was more prominent when used in combination with XL147 (Fig.…”

“…In addition, dual inhibitors of TORC1 and PI3K have also been shown to induce HER3 expression (23). However, the TORC1 inhibitor rapamycin did not mirror the effect of XL147 or the AKT inhibitor 5J8 on HER3 mRNA (Fig.…”

HER3 intracellular domains play a crucial role in HER3/HER2 dimerization and activation of downstream signaling pathways

“…Aberrant activation of HER receptors can tip the balance and cause deteriorative effects on cellular events that lead to various diseases such as cancer (Shepard et al, 2008). Among all the homodimer and heterodimer pairs, HER3/HER2 is the most potent partner for activation of the PI3K/AKT signaling cascade through direct HER3 binding to the p85 subunit of PI3K (Mattoon et al, 2004;Suenaga et al, 2005;Amin et al, 2010b). Growing evidence suggests that HER3 plays a pivotal role in regulation of the HER signaling cascade and it is emerging as a cancer drug target (Engelman et al, 2007;Kong et al, 2008;Wheeler et al, 2008;Baselga and Swain, 2009;Narayan et al, 2009; © Higher Education Press and Springer-Verlag Berlin Heidelberg 2012 Schoeberl et al, 2009;Amin et al, 2010a).…”

Disentangling Multidimensional Spatio-Temporal Data into their Common and Aberrant Responses

“…where we defineL rpca L rpca Figure 4 shows statistics of both RPCA and RP-RPCA (in which RPCA is applied to the matrix Y) as a function of the tuning parameter λ in equation (4). In this example, λ * = 1/ max(q, n · N T ) = 1/ √ 50.…”

“…These data sets have the advantage of being able to identify dynamic relationships between genes or neurons since the spatiotemporal pattern results from integration of regulatory signals or electrochemical signals through the network over time. For example, time series gene-knockout experiment data sets provide the distinct possibility of observing the cellular mechanisms in action [4]. Also, these data sets help us to unravel the mechanistic drivers characterizing cellular response and to break down the genome into sets of genes involved in the related processes [5].…”