The HER2:HER3 dimer is the most potent oncogenic HER dimer

Although HER2 can dimerize with any HER family member, preclinical studies suggest that HER2:HER3 is the most potent oncogenic HER pair and may play a key role in disease progression.⁴ While HER2 activates the MAPK pathway, HER3 is the only receptor that can directly activate the PI3K (phosphatidylinositol 3-kinase) pathway. Therefore, activation of this dimer results in the activation of both the cell proliferation and cell survival pathways, ultimately resulting in tumor cell growth when HER2 is overexpressed.^2,14

Overactive dimerization of HER2 and HER3 leads to increased tumorigenesis

• Abnormal MAPK signaling results in the activation of the tumor cell proliferation pathway¹²
• Increased HER3-mediated PI3K signaling results in the activation of cell survival mechanisms and resistance to apoptosis¹⁴
• Preclinical studies show that this may allow for continued tumor cell survival signaling, even when HER2-mediated signaling is inhibited⁷

The HER2:HER3 dimer may be crucial for the aggressive tumor growth seen in HER2+ breast cancer.⁵

MAPK signaling

• HER2-mediated MAPK signaling is responsible for several key cellular functions, including cell proliferation, migration, differentiation, and angiogenesis^15,16
• Following HER2 activation, adapter molecules are recruited to the membrane to initiate a signaling cascade that results in phosphorylation and activation of MAPK and, ultimately, increased cell proliferation¹⁶

PI3K signaling

• Activation of PI3K is mediated by HER3, and its primary role is to recruit Akt and mTOR to regulate cell survival signaling¹⁷
• Continued PI3K signaling leads to continued tumor cell survival and the possibility for disease progression¹²