The role of Her-2 in penile squamous cell carcinoma progression and cisplatin chemoresistance and potential for antibody-drug conjugate-based therapy

Abstract

Background: Cisplatin-based chemotherapy has been the first choice for advanced penile squamous cell carcinoma (PSCC) in the last decade, but its utility is limited by the low response rate, systemic toxicity, and chemoresistance, which contribute to a poor prognosis. There is no standard second-line therapy for advanced PSCC. Human epidermal growth factor receptor 2 (Her-2)-targeted antibody-drug conjugates (ADCs) are novel low-toxicity agents which have greatly improved clinical outcomes for several advanced cancers. We aimed to explore the expression pattern, clinical significance, and oncogenic roles of Her-2 and the therapeutic potential of Her-2-targeted ADCs in PSCC.

Methods: Her-2 immunohistochemistry was performed for the largest single-centre PSCC cohort to date (367 patients). PSCC cell lines, cisplatin-resistant cell lines, subcutaneous xenograft, and footpad metastatic models were used to investigate the biological roles of Her-2 in PSCC progression. Cytotoxicity, apoptosis assays, and western blotting investigated the mechanism of Her-2 induced cisplatin-chemoresistance. The efficacy of Disitamab Vedotin (RC48), a Her-2-targeted ADC, was evaluated in PSCC.

Results: Her-2 was identified as an adverse prognostic indicator associated with advanced Tumor-Node-Metastasis (TNM) stages and poor survival with an immunohistochemical expression rate of approximately 47.7% (1+, 23.2%; 2+, 18.0%; 3+, 6.5%) in PSCC. Her-2 promotes cell proliferation, migration, invasion, tumour progression, and cisplatin resistance in PSCC. Mechanistically, Her-2 inhibits cisplatin-induced cell apoptosis by the activation of Akt phosphorylation at Ser473 and disrupts the balance between proapoptotic and antiapoptotic proteins. Meanwhile, cisplatin-resistant PSCC cells present aggressive oncogenic abilities and Her-2 upregulation. More importantly, RC48 displayed remarkable antitumor activities in both Her2-positive and cisplatin-resistant PSCC tumours.

Conclusion: Our study suggests that Her-2 is an available therapeutic biomarker for PSCC. Her-2-targeted ADC might have the potential to improve clinical outcomes in high-risk Her-2-positive advanced PSCC patients and provide precious second-line clinical choice for appropriate cisplatin-based chemoresistance patients.

Keywords: ADCs; Apoptosis; Cisplatin resistance; Her-2; Penile cancer.