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 to2,3:

  • 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 receptor5,6

  • 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

The importance of selectively targeting HER2

HER = human epidermal growth factor receptor.

References: 1. Ruiz-Saenz A, Moasser MM. Targeting HER2 by combination therapies. J Clin Oncol. 2018;36(8):808-811. doi:10.1200/JCO.2017.77.1899 2. Luque-Cabal M, García-Teijido P, Fernández-Pérez Y, Sánchez-Lorenzo L, Palacio-Vázquez I. Mechanisms behind the resistance to trastuzumab in HER2-amplified breast cancer and strategies to overcome it. Clin Med Insights Oncol. 2016;10(suppl 1):21-30. doi:10.4137/CMO.S34537 3. Rexer BN, Arteaga CL. Intrinsic and acquired resistance to HER2-targeted therapies in HER2 gene-amplified breast cancer: mechanisms and clinical implications. Crit Rev Oncog. 2012;17(1):1-16. doi:10.1615/critrevoncog.v17.i1.20 4. Scheuer W, Friess T, Burtscher H, Bossenmaier B, Endl J, Hasmann M. Strongly enhanced antitumor activity of trastuzumab and pertuzumab combination treatment on HER2-positive human xenograft tumor models. Cancer Res. 2009;69(24):9330-9336. doi:10.1158/0008-5472.CAN-08-4597 5. Scaltriti M, Verma C, Guzman M, et al. Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity. Oncogene. 2009;28(6):803-814. doi:10.1038/onc.2008.432 6. Maruyama T, Mimura K, Izawa S, et al. Lapatinib enhances herceptin-mediated antibody-dependent cellular cytotoxicity by up-regulation of cell surface HER2 expression. Anticancer Res. 2011;31(9):2999-3005.