The Role of HER3 and NRG1 in Oncology

Joan Garrett, PhD, University of Cincinnati College of Medicine, Ohio, discusses the role of HER3 receptor tyrosine kinase and HER3-targeted agents in cancer treatments. This includes NRG1, the gene encoding the high-affinity HER3 ligand neuregulin 1.

For HER3-targeted agents, Dr Garrett highlighted, “the best hope is identifying the correct patient population,” such as with the HER2/HER3 bispecific antibody zenocutuzumab which requires patients to have an NRG1 fusions-positive cancer.

Transcript:

Hi, my name is Joan Garrett. I'm an associate professor at the College of Pharmacy at University of Cincinnati.

Can you give an overview of the role of HER3 in oncology?

Sure. HER3 was first identified in the late 1980s, and HER3 is a member of the EGFR or ERBB family. Family members include EGFR, HER2, HER3, and HER4. EGFR and HER2 are really well known as being oncogenes, driving cancer growth and different cancer types. HER3 had really previously been an understudied area, studying this protein. But there's definitely a wealth of data showing that HER3 can play a role as an oncogene.

And actually, excitingly, just in December of 2024, there was an FDA approval for a targeted agent, a HER2/HER3 bispecific antibody that's been indicated for patients with lung cancer and pancreatic cancer that have neuregulin 1 fusions.

There are definitely papers that have shown that doing immunohistochemistry of different tumor types, that patients that overexpress HER3 or have increased levels of HER3 a s assessed by immunohistochemistry, they have a worse prognosis. However, unfortunately there's not a standardization for assessing HER3 levels. There is a lack of continuity with these publications, but there's definitely a trend that HER3 overexpression in tumors is associated with a worse prognosis.

What is the role of NRG1 within cancer and how does it relate to HER3?

HER3’s high-fitting ligand is neuregulin 1. In terms of the actual signaling, neuregulin binds to HER3, this induces confirmational changes within HER3, and now, upon neuregulin binding, HER3 can now dimerize or bind to other proteins like EGFR and HER2. In terms of what's known about neuregulin 1, there's been many clinical trials examining, looking at HER3-targeted agents, if they express NRG1, is there a better outcome? I would say the results of that are mixed. It’s not necessarily. There hasn't been an FDA approval for tumors that are neuregulin 1 positive.

However, excitingly, as I mentioned, that there's an FDA approval for a HER2/HER3 bispecific antibody. And so these are specifically in patients that have NRG1 fusions. It’s pretty rare, only 1% of all cancer patients have an NRG1 fusion. But by having these NRG1 fusions, what happens is that typically the fusion partner is anchored at the membrane. So, basically what you're doing, is having lots of neuregulin 1 in these tumors that have neuregulin 1 fusions that will activate HER3, and so these NRG 1 fusions, only 1% of all tumors have this neuregulin 1 fusion, but they're eligible for this HER2/HER3 bispecific antibody.

Where do you see the future of HER3 within cancer research?

There's been many clinical trials examining HER3 monoclonal antibodies, unfortunately, they haven't been successful. And I do think that really the best hope is identifying the correct patient population. The review that we wrote really talked about how other bispecific antibodies failed in clinical trials, and it was really targeting that specific patient population that has neuregulin 1 fusions, that because they have neuregulin 1 fusions that HER3 ligand is always ready to bind HER3 and activate HER3. So, it really seems like the best hope is going to be identifying the correct patient population.

Another patient population that has showed a lot of promise is non-small cell lung cancer patients that have EGFR mutations and have failed with EGFR-targeted therapy. There are phase 3 clinical trials ongoing looking at patritumab deruxtecan assessing the efficacy of this. And those trials are ongoing still, but I think that the correct patient population, whether it's patients that have neuregulin 1 fusions, or whether it's patients that have an EGFR mutation that have failed upon EGFR targeted therapy, I think it's identifying the correct patient population.

Where do patients with HER2-positive cancers fit in?

There's so many approved HER2-targeted agents. I'd say there's a lot of competition with that, because there's so many HER2-directed agents that, it's not completely efficacious, but there's a lot of competition with HER2-targeted agents. It’s not necessarily specifically looking at HER2-positive patients but trying to identify the best patient population that will respond to HER3 therapy.

Is there anything else you’d like to add about this research or this topic?

I think that the take home messages, I've already reiterated, identifying the correct patient population where HER3-targeted agents would be efficacious. But I think the most exciting things are bispecific antibodies, as well as antibody-drug conjugates. I think these are these drug modalities that are up-and-coming fields, and there's a lot of promise for improved patient outcomes.

Source:

Garrett J, Tendler S, Feroz W, Kilroy MK, and Yu H. Emerging importance of HER3 in tumorigenesis and cancer therapy. Nat Rev Clin Oncol. 2025;22:348-370. doi:10.1038/s41571-025-01008-y