Targeting PI3Kα/δ and the ErbB Family of Protein-Tyrosine Kinases in Cisplatin-Resistant Head and Neck Squamous Cell Carcinomas

Abstract

<h3>Purpose/Objective(s)</h3> The mortality rate for advanced head and neck squamous cell carcinoma (HNSCC) remains very high due to cancer recurrence and metastasis. Cisplatin is a commonly used anti-cancer drug for treatment of recurrent and metastatic HNSCC, but the majority of patients will eventually develop resistance. Therefore, there is an urgent, yet still unmet, need for improved therapies for cisplatin-resistant HNSCC. Increasing evidence has demonstrated that ErbB family kinase and PI3K/Akt are the most important regulators and targets in HNSCC. Our goal is to find new therapeutics to treat cisplatin resistant HNSCC without use of cisplatin. Here, we determined the efficacy of a combination of the PI3Kinase inhibitor, Copanlisib with the ErbB inhibitor, Afatinib, on suppressing cisplatin resistant HNSCC <i>in vitro</i> and <i>in vivo</i>. <h3>Materials/Methods</h3> Both cisplatin sensitive (Cal27 and FaDu) and resistant (Cal27CP and FaDu-CP) HNSCC cells were treated with copanlisib, afatinib, or a combination of copanlisib and afatinib. The effects on cell signaling pathways were tested by Western blot assay and RT-PCR. Cell proliferation was determined by MTT assay. Apoptosis was assayed by Annexin V. Migration and invasion was monitored via the xCELLigence real-time cell system tic cells. Xenograft tumor formation was observed in nude mice. <h3>Results</h3> We found that the combination of Copanlisib and Afatinib completely blocked PI3K/Akt/mTOR pathways and ErbB kinase family and significantly suppressed cell proliferation, survival, migration, and invasion <i>in vitro</i>, as well as xenograft tumor formation in animals. <h3>Conclusion</h3> We found that the combination of Copanlisib and Afatinib completely blocked PI3K/Akt/mTOR pathways and ErbB kinase family and significantly suppressed cell proliferation, survival, migration, and invasion <i>in vitro</i>, as well as xenograft tumor formation in animals.