Targeting PI3Kalpha beta and the ErbB family of protein-tyrosine kinases in cisplatin-resistant head and neck squamous cell carcinomas (HNSCC)

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PROJECT SUMMARY: The mortality rate for advanced head and neck squamous cell carcinoma (HNSCC) remains very high due to cancer recurrence and metastasis. Cisplatin is the most commonly used anti-cancer drug for treatment of recurrent and metastatic HNSCC, but the majority of patients will eventually develop resistance to this treatment and die within one year. Therefore, there is an urgent, yet still unmet, need for improved therapies for cisplatin- resistant HNSCC. A major advancement in the treatment of advanced HNSCC in the past 20 years has been the use of the FDA-approved EGFR antibody, Cetuximab. Patients respond well to the Cetuximab-based combination therapies, but they result in only 2-3 months improvement in overall survival. Abnormal activation of key survival pathways through compensatory mechanisms often leads to therapeutic failure of cisplatin and EGFR inhibitors. A most important downstream target of EGFR in head and neck cancer is PI3K. EGFR and other receptor proteins activate PI3K (PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ), which then initiate activation of Akt and mTOR to promote tumor growth, metastasis, and therapy resistance. In fact, PI3Kα mutation and amplification was found in more than 30% of tumors in patients. Therefore, PI3K/Akt/mTOR is a most attractive therapeutic target in HNSCC. However, although many pan- and isoform-specific PI3K inhibitors have been identified, none have been effective for therapeutic use in the clinical setting due to poor effective results and intolerable toxicity caused by the pan-PI3K inhibitors. Thus, it is urgent to find effective PI3K inhibitors for HNSCC therapy. We recently explored simultaneous blockage of ErbB family and PI3K pathways. We used PI3Kα/δ inhibitor Copanlisib, recently approved by the FDA for treatment of elapsed/refractory follicular lymphoma, and pan-ErbB family inhibitor Afatinib, and found that the combination completely blocked PI3K/Akt/mTOR pathways and significantly suppressed cell proliferation, survival, migration, and invasion in vitro, as well as xenograft tumor formation in animals. Our data suggest a new potential therapeutic strategy that targets the PI3Kα/δ and ErbB family to treat cisplatin-resistant HNSCC. To test our hypothesis, we will: (1) determine the significance and requirement of PI3K isoforms to regulate activation of the Akt/mTOR pathway, and tumor growth, metastasis, and resistance to EGFR inhibitor; (2) analyze the FOXO3a-dependent and independent up-regulation of HER3 upon treatment with different PI3K inhibitors and the role(s) of HER3 to confer PI3K inhibitor resistance; and, (3) discover the therapeutic potential of the ErbB family and PI3K to co-target cisplatin-resistant HNSCC treatment in multiple mouse models. Completion of this project will provide important insights into how to effectively treat cisplatin-resistant metastatic HNSCC.