Beyond EGFR inhibition in Head and Neck Squamous Cell Carcinoma: overcoming resistance mechanisms and novel therapeutic frontiers - PubMed
7 days ago
- #EGFR resistance
- #novel therapies
- #HNSCC
- Head and Neck Squamous Cell Carcinoma (HNSCC) is a significant global health challenge with EGFR overexpression in most cases.
- Cetuximab is the only approved EGFR-targeted agent for HNSCC but faces resistance mechanisms like EGFR mutations and compensatory RTK activation.
- Resistance mechanisms include downstream pathway alterations (e.g., PIK3CA mutations, PTEN loss), EMT, and immunosuppressive tumor microenvironment factors.
- Emerging strategies to overcome resistance include dual EGFR inhibition, combination with new targeted agents, and immunomodulation.
- Promising preclinical and early-phase clinical activity seen with irreversible pan-HER TKIs (afatinib, dacomitinib) and dual-target bispecific antibodies (e.g., duligotuzumab, petosemtamab).
- Intratumoral EGFR antisense DNA (EGFR-AS) shows synergy with cetuximab and radiotherapy in preclinical models and phase I trials.
- Future efforts should focus on biomarker-driven patient selection and combination strategies to enhance efficacy and response durability.