EGFR co-targeting and nanotechnology offer new triple-negative breast cancer therapies

Triple-negative breast cancer (TNBC) remains one of the most challenging forms of breast cancer to treat because it lacks the estrogen, progesterone and HER2 receptors that enable targeted treatment in other breast cancer subtypes. A review published in Genes & Diseases examines how targeting the epidermal growth factor receptor (EGFR) alongside other molecular targets, supported by nanocarrier-based delivery, could offer new possibilities for more precise TNBC treatment.

EGFR has attracted particular attention because it is overexpressed in approximately half of TNBC and inflammatory breast cancer cases and is associated with pathways that promote tumor growth, survival and metastasis. Yet treatments directed solely at EGFR have produced limited clinical benefits. The review highlights tumor heterogeneity, inadequate patient selection and resistance mechanisms as important factors that may help explain these disappointing outcomes.

One important consideration is that EGFR expression differs substantially among TNBC subtypes. The review describes the highest EGFR expression in basal-like BL1/2 tumors, followed by mesenchymal and mesenchymal stem-like, immunomodulatory and luminal androgen receptor subtypes. These differences suggest that identifying the molecular characteristics of an individual tumor could be essential for determining whether EGFR-directed treatment is appropriate.

Rather than targeting EGFR alone, the article explores co-targeting strategies involving molecules that may contribute to tumor progression, proliferation and metastasis. Analysis of EGFR-high and EGFR-low TNBC samples identified 96 genes with substantially increased transcription in EGFR-high tumors. Potential co-targeting candidates discussed include FABP4, MMP9, MMP14, VCAM1, CCN4 and CDK4/6, pointing toward treatment strategies designed around multiple vulnerabilities rather than a single molecular target.

A central challenge is delivering multiple therapeutic agents efficiently and selectively. Here, nanotechnology could provide an important advantage. Nanocarriers including liposomes, dendrimers and other nanoparticles can transport combinations of antibodies, tyrosine kinase inhibitors and small interfering RNAs (siRNAs). Such systems may improve drug stability, bioavailability and tumor specificity while enabling two or more therapeutic agents to reach the same target site.

The review ultimately presents EGFR co-targeting as a promising direction for precision treatment of TNBC, while emphasizing that appropriate molecular signatures must first be identified and validated. Combining careful tumor classification with multi-target therapies and nanocarrier delivery could help overcome resistance and expand therapeutic options for patients with aggressive EGFR-positive cancers.