However, its utility is limited by the low response rate, systemic toxicity, and chemoresistance, which contribute to a poor prognosis. For PSCC patients who progress on these regimens, no available standard second-line regimen was recommended, and the prognosis remains poor with a median OS of less than 6 months. Therefore, the exploration of potential targets and corresponding safe and effective therapeutic strategies is urgently needed for advanced PSCC patients.
Her-2, as a classical unfavorable prognostic biomarker, contributes to cell cycle arrest, apoptosis inhibition, and chemoresistance in the majority of tumors, and anti-HER2 therapies especially HER2-ADCs drugs with advantages of low toxicity and precise targeting effects have achieved great success in HER2-positive breast gastric, and bladder cancers. Besides, previous sequencing studies have suggested that Her-2 amplification is the second most frequent genetic alteration; it occurs in 4%-6% of PSCC patients and has a higher rate of approximately 10% in those with advanced disease.7,8 This result indicates that Her-2 is an available therapeutic target in PSCC, but large-scale IHC staining evidence is lacking.
For these reasons, we aimed to explore the expression pattern, clinical significance, and oncogenic roles of Her-2 and the therapeutic potential of anti-Her-2 therapy in PSCC. We demonstrated that Her-2 is an adverse prognostic factor with an immunohistochemical expression rate of approximately 47.7% (1+, 23.2%; 2+, 18.0%; 3+, 6.5%) associated with advanced TNM stages and poor survival. Her-2 inhibited cisplatin-induced apoptosis by activating Akt phosphorylation at Ser473 and disrupting the balance between proapoptotic and antiapoptotic proteins, thereby promoting tumor progression and cisplatin chemoresistance. Meanwhile, cisplatin-resistant PSCC cells present aggressive oncogenic abilities and Her-2 upregulation. More importantly, Her-2-targeted ADC such as Disitamab Vedotin (RC48) displayed remarkable antitumor activities in both Her2-positive and cisplatin-resistant PSCC tumors. The results provided innovative therapeutic strategies to improve clinical outcomes in high-risk Her-2-positive advanced PSCC patients and create a hard-won second opportunity for patients with cisplatin-based chemoresistant advanced PSCC patients.
Written by: Xingliang Tan,1,2,3 Kai Yao1,2,3
- Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in Southern China, Guangzhou, China
- Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
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