Simultaneous HER2 Inhibition May Enhance the HER2 Blockade¹

What is simultaneous HER2 inhibition?

Simultaneous inhibition happens when 2 complementary HER2 inhibitors block HER2 signaling both at the cell surface and within the tumor cell.¹

Targeting HER2 extracellularly

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

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

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 antitumor activity.^4-6

• In xenograft models, using 2 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 the HER2 tyrosine kinase domain enhances extracellular antibody-dependent cellular cytotoxicity (ADCC)

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