Preclinical and Clinical Characterization of Fibroblast-derived Neuregulin-1 on Trastuzumab and Pertuzumab Activity in HER2-positive Breast Cancer

Abstract

Purpose: To characterize expression of neuregulin-1 (NRG1), an HER3 ligand, in HER2-positive breast cancer and its relation with the efficacy of trastuzumab with or without pertuzumab. Experimental Design: Characterization of NRG1 expression in tumor cell lines, in tumor specimens, and in cancer-associated fibroblasts (CAFs). Patient-derived CAFs were used to investigate NRG1 impact on the activity of trastuzumab with or without pertuzumab in HER2-positive breast cancer cells. The relationship between NRG1 expression and pathologic response to anti-HER2–based neoadjuvant therapy was assessed in a retrospective patient cohort and in the NeoSphere trial. Results: NRG1 was expressed in HER2-positive breast cancer–derived fibroblasts at significantly higher levels than in cancer cells. NRG1 and the conditioned media (CM) from CAFs phosphorylated HER3 and AKT in cancer cells and mediated trastuzumab resistance. Stable genetic depletion of NRG1 from CAFs overcame trastuzumab resistance. Pertuzumab effectively suppressed trastuzumab resistance mediated by either NRG1 or CAF's CM. NRG1 engaged an epithelial-to-mesenchymal transition that was prevented by trastuzumab and pertuzumab. In clinical samples, stromal and/or tumor cell expression of NRG1 determined by immunohistochemistry was uncommon (13.2%) yet significantly linked with residual disease following trastuzumab-based neoadjuvant therapy. In the NeoSphere trial, the magnitude of the difference of pathologic complete response rates favoring the pertuzumab arm was higher in the NRG1-high group. Conclusions: CAF-derived NRG1 mediates trastuzumab resistance through HER3/AKT, which might be reverted by pertuzumab. In patients with HER2-positive breast cancer, high expression of NRG1 was associated to poor response to trastuzumab, but not in combination with pertuzumab.

Spatial Transcriptomic and Metabolomic Landscapes of Oral Submucous Fibrosis‐Derived Oral Squamous Cell Carcinoma and its Tumor Microenvironment

“…In OSF‐derived OSCC, immune cells can express membrane MHC class II molecule HLA‐DPB1 and bind to neuregulin‐1 (NRG1) molecules on the surface of CAF1 cells, potentially influencing the EMT and fibrosis processes. [ 61 , 62 ] Besides, CAF1‐like tumor cells located at the leading edge can adhere immune cells through ligand–receptor pairs such as COL1A1/a1b1 , COL1A2/a1b1 , and COL3A1/a1b1 complex , thereby limiting the migration of immune cells into the tumor tissue. [ 63 , 64 ] Moreover, the ligand–receptor interactions between CAF1‐like tumor cells and epithelial cells (e.g., COL1A1 / a2b1 , COL1A2 / a2b1 complex , and FN1 / a3b1 complex ) strengthen the immune barriers represented by collagen fibril within the Tumor region, blocking immune cell infiltration and assisting in immune evasion of OSF‐derived OSCC.…”

Adipocyte Precursor-Derived NRG1 Promotes Resistance to FGFR Inhibition in Urothelial Carcinoma

“…Therefore, the enrichment of NRG1-secreting stroma in the TME could be a negative predictive biomarker for erdafitinib single-agent therapy. These tumors may be the prime candidates for our proposed combination therapy of erdafitinib and pertuzumab ( 66 ). Moreover, because obesity results in a higher frequency of ADSCs, and an altered ADSC biology towards increased protumorigenic signaling ( 67, 68 ), our proposed combination therapy could be even more relevant in obese patients.…”

DLDH-containing extracellular vesicles from CAFs reduced DOX sensitivity in triple-negative breast cancer

“…CAFs/TNBC induced stemness features of tumor cells and decreased sensitivity to docetaxel via the secretion of FGF5 and production of brillar collagen [34]. And CAFs from HER2 + BC patients directly contributed to trastuzumab resistance through secreted high levels of NRG1 and activated HER3/AKT pathway [35]. In addition, CAFs could secrete EVs to transfer intracellular components to cancer cells and modify their treatment resistance.…”