Her-2 promoting tumor progression and cisplatin resistance as a novel therapeutic target in penile squamous cell carcinoma.

Authors

Xingliang Tan

Xingliang Tan

Sun Yat-Sen University Cancer Center, Guangzhou, China

Xingliang Tan , Kai Yao

Organizations

Sun Yat-Sen University Cancer Center, Guangzhou, China, Department of Urology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China

Research Funding

Other Foundation
Natural Science Foundation of Guangdong Province, China, No. 2022A1515012318

Background: Cisplatin-based chemotherapy has been the first choice for advanced penile squamous cell carcinoma (PSCC) in the last decade, but remains challenging owing the unsatisfied response rates, frustrating systemic toxicity and chemoresistance leading to poor prognosis. There is no standard second-line therapy for advanced PSCC. Antibody-drug conjugates (ADC) were novel targeted and low-toxicity agents, of which Her-2 targeted ADCs widely used and have greatly improved clinical outcomes in breast, gastric and bladder cancers. We aimed to explore the expression pattern, clinical significance, oncogenic roles of Her-2 and the therapeutic potentiality of Her-2 target ADCs in PSCC. Methods: The immunohistochemical expression of Her-2 was detected in the largest single center cohort of 367 PSCC patients up to date. PSCC cell lines, cisplatin-resistant cell lines and animal models were established to investigated the biological roles of Her-2 in PSCC progression and cisplatin chemoresistance. Disitamab vedotin (RC48), an Her-2 targeted ADC drug, was used to evaluate the efficiency in PSCC. Results: Her-2 was an unfavourable prognostic indicator with around 47.7% immunohistochemical expression rate (1+, 23.2%; 2+, 18.0%; 3+, 6.5%) in PSCC. Her-2 positive immunohistochemical expression (2+/3+) was associated with advanced pT, pN stages, metastasis and poor overall survival (positive vs. negative, HR (95%Cl): 3.133 (2.120-4.631), p=0.000). Cellular and animal experiments confirmed that Her-2 promoted tumor progression, inhibited cisplatin-induced cell apoptosis via Akt pathways and increased cisplatin resistance in PSCC. Meanwhile, cisplatin-resistant PSCC cells up-regulated Her-2 expression. More importantly, Her-2 targeted ADCs Disitamab Vedotin displayed remarkable anti-tumor activities both in Her2-positive and cisplatin-resistant PSCC tumors. Conclusions: Our study suggested that Her-2 was an available therapeutic biomarker in PSCC. Targeting Her-2 ADCs might be a prospective option to improve clinical outcomes in high-risk Her-2 positive advanced PSCC patients and provided precious opportunity for cisplatin-based chemoresistance patients.

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Abstract Details

Meeting

2023 ASCO Breakthrough

Session Type

Poster Session

Session Title

Poster Session A

Track

Breast Cancer,Central Nervous System Tumors,Developmental Therapeutics,Genitourinary Cancer,Hematologic Malignancies,Thoracic Cancers,Other Malignancies or Topics

Sub Track

Antibody Drug Conjugates

Citation

JCO Global Oncology 9, 2023 (suppl 1; abstr 67)

DOI

10.1200/GO.2023.9.Supplement_1.67

Abstract #

67

Poster Bd #

D3

Abstract Disclosures