Blocking NRG1 and Other Ligand-Mediated Her4 Signaling Enhances the Magnitude and Duration of the Chemotherapeutic Response of Non–Small Cell Lung Cancer

Abstract

Although standard chemotherapies are commonly used to treat most types of solid tumors, such treatment often results in inadequate response to, or relapse after, therapy. This is particularly relevant for lung cancer because most patients are diagnosed with advanced-stage disease and are treated with frontline chemotherapy. By studying the residual tumor cells that remain after chemotherapy in several in vivo non-small cell lung cancer models, we found that these cells have increased levels of human epidermal growth factor receptor (HER) signaling due, in part, to the enrichment of a preexisting NRG1(HI) subpopulation. Neuregulin 1 (NRG1) signaling in these models can be mediated by either the HER3 or HER4 receptor, resulting in the differential activation of downstream effectors. Inhibition of NRG1 signaling inhibits primary tumor growth and enhances the magnitude and duration of the response to chemotherapy. Moreover, we show that inhibition of ligand-mediated Her4 signaling impedes disease relapse in cases where NRG1 inhibition is insufficient. These findings demonstrate that ligand-dependent Her4 signaling plays an important role in disease relapse.

Intratumoral Heterogeneity: From Diversity Comes Resistance

“…Our laboratory found that primary NSCLCs contain a small subpopulation of NRG1 þ cells and that NRG1 and its receptors HER3 and HER4 are enriched in residual tumor cells that survive chemotherapy treatment. Moreover, inhibition of NRG1 signaling enhanced the magnitude and duration of the response to chemotherapy in several in vivo models (29). Recent studies highlight the impact of intratumoral heterogeneity in NRG1 and HER3 expression in breast cancer.…”

“…Trials are currently under way to assess whether the endocrine therapy index of CTCs is correlated with patient outcome (28). Heterogeneous expression of the ERBB3 (HER3) and its ligand NRG1 have been reported in a variety of human cancers, including breast cancer, lung cancer, and glioblastoma (23,29,30). HER3 signals as heterodimer with other receptors of the HER family leading to potent activation of the PI3K/AKT pathway (22).…”

Dual Targeting of HER2-Positive Cancer with Trastuzumab Emtansine and Pertuzumab: Critical Role for Neuregulin Blockade in Antitumor Response to Combination Therapy

“…In addition to growth factor regulation of cell proliferation and differentiation, recent reports show an important role for multiple RTK ligands in resistance to kinase inhibitors (7)(8)(9). The HER3 ligand, neuregulin 1 (NRG-1), was recently shown to mediate resistance to chemotherapeutic agents as well (10). Moreover, HER3 was reported to mediate resistance to EGFR, HER2, and PI3K inhibitors.…”

Emerging anti-cancer antibodies and combination therapies targeting HER3/ERBB3

“…Some of the mAbs show synergy with chemotherapy on lung cancer cells. 88 Notably, because NRG1 binds both HER3/ERBB3 and HER4/ERBB4, and the latter receptor is expressed in cardiac and neural tissues, toxicity might become an issue when targeting NRGs. Another way to target the ligands is a decoy receptor strategy.…”

“…100 1) The ligand trapping strategy consists of developing recombinant decoys (aka TRAP). 89 or anti-NRG antibodies, 88 thereby avoiding ligand-induced activation of HER3. (2) Since HER3 homodimers are weakly active compared to the heterodimers HER3-HER2 and HER3-EGFR, a recombinant bivalent-NRG has been developed that locks HER3 in the homodimeric conformation and restricts its ability to form heterodimers.…”