Human epidermal growth factor receptor 2 and Programmed cell death protein 1 (HER2 and PD-1)

The combination of Human Epidermal Growth Factor Receptor 2 (HER2) and Programmed Cell Death Protein 1 (PD-1) represents a synergistic therapeutic strategy targeting both tumor-intrinsic signaling and the immune microenvironment. HER2 (ERBB2) is a receptor tyrosine kinase that, when overexpressed or mutated, promotes uncontrolled cell proliferation and survival in cancers such as breast, gastric, and gastroesophageal junction adenocarcinomas [1, 3]. PD-1 (PDCD1) is an inhibitory checkpoint receptor expressed on T cells that, upon binding its ligands (PD-L1/PD-L2), suppresses T-cell activation and allows tumors to evade immune detection [2, 4]. Drugs targeting HER2, such as trastuzumab, can induce antibody-dependent cellular cytotoxicity (ADCC) and release tumor antigens, which potentially primes the immune system for a more robust response when combined with PD-1 inhibitors like pembrolizumab [3, 4]. This dual approach aims to overcome resistance to HER2-targeted monotherapy by reinvigorating exhausted T cells within the tumor microenvironment [4]. Clinical trials, such as KEYNOTE-811, have demonstrated that combining these targets significantly improves outcomes in HER2-positive metastatic disease [3]. Sources: [1] UniProt P04626; [2] UniProt Q15116; [3] Janjigian YY, et al. (2021) Nature; [4] Loi S, et al. (2019) Lancet Oncology.

Other names

ERBB2 and PDCD1HER2/neu and CD279CD340 and PD-1HER2 and PDCD1Receptor tyrosine-protein kinase erbB-2 and Programmed cell death protein 1

Dual-pathway modulation involving the inhibition of HER2-mediated oncogenic signaling and the blockade of the PD-1/PD-L1 immune checkpoint axis. HER2 inhibition leads to decreased cell proliferation and increased ADCC, while PD-1 blockade prevents T-cell exhaustion, collectively enhancing the anti-tumor immune response.