Sustained and complete inhibition of HER3 and its output to PI3K/Akt are required for the optimal antitumor effect of therapeutic inhibitors of the HER2 oncogene. Here, we show that, after inhibition of the HER2 tyrosine kinase with lapatinib, there is PI3K/ Akt and FoxO3a-dependent up-regulation of HER3 mRNA and protein. Up-regulated HER3 was then phosphorylated by residual HER2 activity, thus partially maintaining P-Akt and limiting the antitumor action of lapatinib. Inhibition of HER3 with siRNA or a neutralizing HER3 antibody sensitized HER2+ breast cancer cells and xenografts to lapatinib both in vitro and in vivo. Combined blockade of HER2 and HER3 inhibited pharmacodynamic biomarkers of PI3K/Akt activity more effectively than each inhibitor alone. These results suggest that because of HER3-mediated compensation, current clinical inhibitors of HER2 and PI3K/Akt will not block the PI3K pathway completely. They also suggest that therapeutic inhibitors of HER3 should be used in combination with HER2 inhibitors and PI3K pathway inhibitors in patients with HER2-and PI3K-dependent cancers.T he HER (ErbB) transmembrane receptor tyrosine kinase family is comprised of four members: EGF receptor (ErbB1), HER2 (ErbB2), HER3 (ErbB3), and HER4 (ErbB4). HER2 is amplified in approximately 25% of human breast cancers (1) and is associated with poor prognosis (2). HER2/HER3 heterodimers are the most transforming of this receptor network (3). HER3, which lacks intrinsic kinase activity (4), is able to potently activate the phosphatidylinositol-3 kinase (PI3K)/Akt signaling pathway (5) via its six docking sites for the p85 adaptor subunit of PI3K (6). HER2-mediated transformation of mammary epithelial cells has been attributed to a large degree to activation of the PI3K-Akt survival pathway. Trastuzumab, a monoclonal antibody directed against the ectodomain of HER2, and the EGFR/HER2 tyrosine kinase inhibitor (TKI) lapatinib are approved for the treatment of HER2-overexpressing breast cancer. Although these therapies work by different mechanisms, it has been proposed that, to exert an antitumor effect, they should inhibit phosphorylation of HER3 and disable the PI3K/ Akt pathway (7,8).The HER3 coreceptor plays an essential role in HER2-mediated transformation, tumor progression, and drug resistance. In HER2-dependent cells, loss of HER3 results in reduced signaling through PI3K and cell proliferation (9, 10), suggesting that HER2 may be dependent on HER3 to drive growth and survival of breast cancer cells. As it applies to drug resistance, inhibition of HER2 phosphorylation by TKIs targeting EGFR and HER2 in HER2+ breast cancer cells is followed by feedback upregulation of activated HER3, thus limiting the inhibitory effect of HER TKIs (11,12). These studies point to a central role for HER3 in the survival of HER2+ cells that potentially limit the full action of HER2 antagonists. ResultsInhibition of the HER2 Tyrosine Kinase Is Followed by Up-Regulation of HER3 and P-HER3. We hypothesized that sustained and complete inhibiti...

Mutations in genes that constitute the phosphatidylinositol 3-kinase (PI3K) pathway occur in >70% of breast cancers. Clinical and experimental evidence suggest that PI3K pathway activation promotes resistance to some of the current breast cancer therapies. PI3K is a major signaling hub downstream of human epidermal growth factor receptor (HER)2 and other receptor tyrosine kinases. PI3K activates AKT, serum/glucocorticoid regulated kinase (SGK), phosphoinositide-dependent kinase 1 (PDK1), mammalian target of rapamycin (mTOR), and several other molecules involved in cell cycle progression and survival. In estrogen receptor (ER)+ breast cancer cells, PI3K activation promotes estrogen-dependent and -independent ER transcriptional activity, which, in turn, may contribute to anti-estrogen resistance. Activation of this pathway also confers resistance to HER2-targeted therapies. In experimental models of resistance to anti-estrogens and HER2 inhibitors, pharmacological inhibition of PI3K/AKT/mTOR has been shown to overcome drug resistance. Early clinical data suggest that combined inhibition of either HER2 or ER plus inhibition of the PI3K pathway might be an effective strategy for treatment of respective HER2+ and ER+ breast cancers resistant to standard therapies. Here, we review alterations in the PI3K pathway in breast cancer, their association with therapeutic resistance, and the state of clinical development of PI3K pathway inhibitors.

ERBB family members including epidermal growth factor receptor (EGFR) also known as HER1, ERBB2/HER2/Neu, ERBB3/HER3 and ERBB4/HER4 are aberrantly activated in multiple cancers and hence serve as drug targets and biomarkers in modern precision therapy. The therapeutic potential of HER3 has long been underappreciated, due to impaired kinase activity and relatively low expression in tumors. However, HER3 has received attention in recent years as it is a crucial heterodimeric partner for other EGFR family members and has the potential to regulate EGFR/HER2-mediated resistance. Upregulation of HER3 is associated with several malignancies where it fosters tumor progression via interaction with different receptor tyrosine kinases (RTKs). Studies also implicate HER3 contributing significantly to treatment failure, mostly through the activation of PI3K/AKT, MAPK/ERK and JAK/STAT pathways. Moreover, activating mutations in HER3 have highlighted the role of HER3 as a direct therapeutic target. Therapeutic targeting of HER3 includes abrogating its dimerization partners’ kinase activity using small molecule inhibitors (lapatinib, erlotinib, gefitinib, afatinib, neratinib) or direct targeting of its extracellular domain. In this review, we focus on HER3-mediated signaling, its role in drug resistance and discuss the latest advances to overcome resistance by targeting HER3 using mono- and bispecific antibodies and small molecule inhibitors.

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