Simultaneous HER2 Inhibition May Enhance the HER2 Blockade¹

What is Simultaneous HER2 Inhibition?

Simultaneous inhibition happens when two complementary HER2 inhibitors block HER2 signaling both at the cell surface and within the tumor cells.¹

Targeting HER2 extracellularly

When targeting HER2 extracellularly alone, resistance develops due to^2,3:

• Reactivation of downstream pathways involved in cell proliferation and growth,
• Compensatory increases in estrogen receptor signaling due to crosstalk

Targeting HER2 intracellularly

While targeting HER2 intracellularly has been shown to reduce HER2 signaling through the HER2/HER3 dimer, any residual HER2 activity results in continued HER2/HER3 signaling and tumor cell growth.^1,3

Potential Benefits of Simultaneous HER2 Inhibition

Several combination strategies have been investigated to enhance HER2 blockade and anti tumor activity.^4-6

• In xenograft models, using two HER2 inhibitors that target the extracellular domain of HER2 results in greater antitumor activity than with either antibody working alone⁴

Inhibition of Intracellular HER2 signaling may potentiate surface expression of the HER2 receptor^5,6

• Preclinical studies demonstrate that intracellular inhibition of HER2 tyrosine kinase domain enhances extracellular antibody-dependent cellular cytotoxicity (ADCC).

Combination HER2-targeting regimens are needed to provide simultaneous extra- and intracellular inhibition.¹