Photo Credit: Ezume Images

The following is a summary of “HER4 and EGFR Activate Cell Signaling in NRG1 Fusion-Driven Cancers: Implications for HER2-HER3-specific Versus Pan-HER Targeting Strategies,” published in the January 2024  issue of Oncology by Udagawa, et al.

NRG1 gene fusions are changes found in NSCLC and other cancers that can be treated. Previous research has shown that NRG1 fusions communicate through HER2 and HER3. However, so far, treatments that focus on HER3 or the communication between HER2 and HER3 have only shown moderate success in people with NSCLC who have NRG1 fusions. NRG1 fusion proteins can bind both HER3 and HER4, but the role HER4 and other HER family members play in NRG1 fusion-positive diseases needs to be clarified. 

Researchers studied the part that HER4 and EGFR-HER3 signals play in NRG1 fusion-positive cancers by using Ba/F3 models that were modified to show different HER family members along with NRG1 fusions, as well as in vitro and in vivo models of NRG1 fusion-positive cancer. They found that NRG1 fusions can increase tumor cell growth and communication through HER4, even when other HER family members are absent. In addition, cells that produce NRG1 fusions also trigger EGFR-HER3 signaling, and these receptors need to be blocked to stop tumor cell growth successfully. 

They demonstrated that using cetuximab, an anti-EGFR antibody, trastuzumab, and pertuzumab, two anti-HER2 antibodies, together had a stronger effect. Also, pan-HER tyrosine kinase inhibitors worked better than tyrosine kinase inhibitors that were more specific for EGFR, EGFR-HER2, or HER2-HER4. However, the dependence on EGFR or HER4 signaling varied between NRG1 fusion-positive diseases. The results showed that blocking HER, including HER4 and EGFR, works better than just targeting HER3 or HER2-HER3 in cancers that are positive for NRG1.

Source: sciencedirect.com/science/article/abs/pii/S155608642300802X