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HER3 Rationale Text Module

CME

Expanding Our Understanding of HER3 Expression, Implications, and Rationale for HER3-Targeted Therapy in Solid Tumors

Physicians: Maximum of 0.50 AMA PRA Category 1 Credit™

Released: October 20, 2023

Expiration: October 19, 2024

Misako Nagasaka
Misako Nagasaka, MD, PhD
CME/CE Information

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HER3: Biology and Role in Oncogenesis

HER3 is a member of the ERBB/HER protein kinase family, which is widely expressed in epithelial, mesenchymal, and neuronal cells.1,2 Although HER3 itself has weak tyrosine kinase activity, it heterodimerizes with other receptor tyrosine kinases, preferentially with EGFR and HER2, to activate oncogenic signaling. These heterodimers signal most strongly through the PI3K/AKT/mTOR pathway but also affect the MAPK, JAK, and SRC pathways.3 Of all HER3 heterodimers, the HER2/HER3 heterodimer is the most biologically active and potent for activating the PI3K/AKT cascade.1 HER2-dependent breast cancers likely rely on HER3 to drive oncogenic signaling.

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HER3 and Neuregulins

Neuregulins 1 and 2 are the primary activating ligands for HER3, promoting heterodimerization with HER2 or EGFR and leading to oncogenic signaling.4 NRG1 gene fusions result in aberrant expression of the NRG1 ligand on the cell surface, leading to pathologic activation of downstream signaling.

NRG1 fusions are rare but found in multiple solid tumors, including colorectal cancer, pancreatic ductal adenocarcinoma, lung adenocarcinoma, cholangiocarcinoma, ovarian cancer, and sarcoma.5 

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HER3 Expression Across Cancer Types

HER3 is expressed ubiquitously in multiple solid tumors, although the frequency of overexpression varies by tumor type.2 HER3 overexpression occurs in colorectal cancer, head and neck squamous cell carcinoma, melanoma, and cancer of the breast, stomach, ovary, prostate, and bladder.1 In a study using an artificial intelligence–powered immunohistochemistry (IHC) analyzer, the highest levels of HER3 expression were observed in colorectal cancer (40.5%), followed by bladder cancer (24.4%), stomach cancer (18.8%), and kidney cancer (13.2%).6

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Assessment of HER3 Expression

HER3 expression level typically is determined using IHC in a manner similar to that used to measure HER2 overexpression, which is shown in the clinical scoring system on this slide. However, standardized definitions for HER3 expression levels have not been established and vary somewhat between tumor types.7 Clinical trials may define HER3 expression levels using an H-score, which is a quantification of IHC staining intensity, or with cutoffs for number of tumor cells expressing HER3.8 HER3 testing is not currently recommended for clinical use. Clinical trials of HER3-targeted agents have varied in their HER3 expression thresholds used as inclusion criteria. 

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Impact of HER3 Overexpression on Outcomes Is Unclear

The impact of HER3 overexpression on outcomes is unclear. In a meta-analysis of 12 studies that included patients with various solid tumor types, HER3 overexpression appeared to be associated with worse survival at 3 years and 5 years.9 However, individual studies rarely show significance.   

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Proposed Role of HER3 in EGFR TKI Resistance

Acquired resistance to EGFR tyrosine kinase inhibitor (TKI) therapy is frequently seen in non-small-cell lung cancer. Molecular studies indicate that HER3 may contribute to EGFR TKI resistance even though it is not a direct target of these agents. Preclinical studies suggest that negative feedback from decreased AKT signaling may lead to increased HER3 phosphorylation and reactivation of the PI3K pathway.10 In one series of preclinical studies, amplification of MET caused resistance to an EGFR TKI by driving HER3-dependent PI3K activation.11 

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EGFR Inhibition Increases HER3 Activity in Colon Cancer Cells

Preclinical studies in colon cancer cell lines also suggest a role for HER3 activity in the setting of EGFR inhibition.12 Treatment of cell lines with the EGFR-targeted monoclonal antibody cetuximab induces phosphorylation of HER3 but not EGFR or HER2. Cetuximab treatment also induces HER2:HER3 dimerization and binding of HER3 to PI3K. Together these data show how upregulation of HER3 may provide a pathway of cellular resistance to EGFR inhibition by allowing the PI3K signaling pathway to continue to function.  

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HER3 Is Involved in Treatment Resistance in Breast Cancer Cells

Other preclinical studies suggest that HER3 contributes to resistance to different types of therapies in breast cancer. In studies of breast cancer cells, short hairpin RNA–mediated knockdown of HER3 expression was found to enhance paclitaxel-induced apoptosis.13 This effect appeared to be mediated through PI3K, AKT, and mTOR. Researchers concluded that HER2/HER3 heterodimerization is required for HER2 activation and that elevated HER3 expression is required for HER2-mediated paclitaxel resistance.

Another study evaluated the importance of HER3 to oncogenic signaling in breast cancer cells that overexpress HER2 but are resistant to the EGFR-HER2 inhibitor lapatinib. In these drug-resistant cells, knocking down HER3 restored the ability of lapatinib to inhibit PI3K and significantly inhibited cell growth and viability.14

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HER3 Expression Increases With Acquired EGFR TKI Resistance in Patients With NSCLC

Exploratory data from clinical studies also has provided insights as to a potential role for HER3 in mechanisms of EGFR TKI resistance.15 In paired tumor samples from patients with EGFR-mutated NSCLC before and after EGFR TKI treatment leading to therapeutic resistance, HER3 expression was higher after acquisition of EGFR TKI resistance. Transcriptome analysis showed an association between HER3 augmentation and repression of PI3K/AKT/mTOR signaling, particularly in patients who received continuous EGFR TKI therapy beyond tumor progression. 

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HER3 as Therapeutic Target in Solid Tumors: Key Takeaways

In summary, HER3 itself has weak tyrosine kinase activity but heterodimerizes with other receptor tyrosine kinases to drive oncogenic signaling, primarily through the PI3K/AKT pathway. HER3 expression is detectable in a range of solid tumor types, including lung, breast, prostate, ovarian, pancreatic, and colorectal cancers. There appears to be a slight association between HER3 overexpression and shorter survival across cancer types. In vitro studies indicate that HER3 contributes to a negative feedback cycle, resulting in restoration of PI3K/AKT signaling following EGFR inhibition. Several models of cancer cell biology indicate that HER3 has an essential role in resistance to EGFR inhibition. Studies in paired tumor samples from patients with EGFR-mutated NSCLC demonstrate an association between HER3 expression and acquisition of EGFR TKI resistance. Together, these findings suggest that HER3 may be a beneficial therapeutic target in multiple solid tumors, particularly in acquired resistance settings. 

Current evidence indicates that HER3 activation primarily drives oncogenic signaling through which of the following pathways?

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