HER2 Amplification in Tumors Activates PI3K/Akt Signaling Independent of HER3

Abstract

Current evidence suggests that HER2-driven tumorigenesis requires HER3. This is likely due to the unique ability of HER3 to activate PI3K/Akt pathway signaling, which is not directly accessible to HER2. By genetic elimination of HER3 or shRNA knockdown of HER3 in HER2-amplified cancer cells, we find residual HER2-driven activation of PI3K/Akt pathway signaling that is driven by HER2 through direct and indirect mechanisms. Indirect mechanisms involved second messenger pathways, including Ras or Grb2. Direct binding of HER2 to PI3K occurred through p-Tyr1139, which has a weak affinity for PI3K but becomes significant at very high expression and phosphorylation. Mutation of Y1139 impaired the tumorigenic competency of HER2. Total elimination of HER3 expression in HCC1569 HER2-amplified cancer cells significantly impaired tumorigenicity only transiently, overcome by subsequent increases in HER2 expression and phosphorylation with binding and activation of PI3K. In contrast to activation of oncogenes by mutation, activation by overexpression was quantitative in nature: weak intrinsic activities were strengthened by overexpression, with additional gains observed through further increases in expression. Collectively, these data show that progressive functional gains by HER2 can increase its repertoire of activities such as the activation of PI3K and overcome its dependency on HER3. The intrinsic ability of HER2 to activate PI3K correlates with increased HER2 expression and can supplant the dependency upon HER3 for growth in HER2-amplified cancers. .

New analysis pipeline for high-throughput domain-peptide affinity experiments improves SH2 interaction data

“…This data has had a wide-reaching effect in many areas of SH2 domain research: the data has been used to draw specific conclusions about SH2 domain biology such as identification of EGFR recruitment targets (33), to explain quantitative differences in RTK signaling (9), and as evidence to understand the promiscuity of EGFR tail binding (34). In addition, this work has been used to guide experimental design by filtering potential binding proteins by affinity (35), to reconcile confusing experimental results (36), and to guide new experimental hypothesis testing (37). It has played a role in cancer research as context to understand kinase dependencies in cancer (38), and as evidence of HER3 and PI3K connections as relevant to PTEN loss in cancer (39).…”

Quantitative proteomic analyses in blood: A window to human health and disease

“…Ruiz‐Saenz et al. used an Ab array approach to investigate phosphorylation of EGFR at various sites and found that HER2‐driven tumorigenesis worked, at least partially, through a gain‐of‐function incurred by amplification and overexpression, with phosphorylation levels of HER2 being a key threshold …”

“…used an Ab array approach to investigate phosphorylation of EGFR at various sites and found that HER2-driven tumorigenesis worked, at least partially, through a gain-of-function incurred by amplification and overexpression, with phosphorylation levels of HER2 being a key threshold. 89 In another study, Krishnamoorthy et al employed a peptide microarray to study the functional significance of phosphoproteins across various signal transduction pathways. They identified endogenous tyrosine-phosphoproteome interaction networks in breast cancer cells mediated by the signaling adaptor protein GRB2, which transduces cellular responses downstream of several RTKs through the Ras-ERK signaling cascade.…”

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“…2). In addition to the high proportion of cancers with PI3K pathway mutations, PI3K activity has been implicated in mediating signals from other driver mutations including RAS (9)(10)(11) and RTKs, such as the human epidermal growth factor receptor, HER2 (12,13). PI3K activation has also been suggested as a mechanism of tumor escape from HER2targeted therapies (14)(15)(16), and combination inhibition of PI3K with HER2 has improved efficacy in preclinical models leading to clinical trials of the combination (17).…”