Simultaneously inactivating Src and AKT by saracatinib/capivasertib co-delivery nanoparticles to improve the efficacy of anti-Src therapy in head and neck squamous cell carcinoma

• Type of Material: Article
• Authors: Liwei Lang, Augusta University; Chloe Shay, Emory University; Xiangdong Zhao, Augusta University; Yuanping Xiong, Augusta University; Xuli Wang, University of Utah; Yong Teng, Emory University
• Language: English
• Date: 2019-12-05
• Publisher: BMC
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s). 2019
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s13045-019-0827-1
• Title of Journal or Parent Work: JOURNAL OF HEMATOLOGY & ONCOLOGY
• Volume: 12
• Issue: 1
• Start Page: 132
• End Page: 132
• Grant/Funding Information: This work was supported in part by NIH grants (R01DE028351-01A1 and R03DE028387) and CURS Summer Scholars (to YT)
• Keywords: Src; Oncology; HNSCC; Science & Technology; AKT; Life Sciences & Biomedicine; Co-delivery nanoparticles; Saracatinib; ACTIVATION; CANCER; FAMILY; INDUCED APOPTOSIS; Hematology; Synergistic effects; EXPRESSION; Capivasertib
• Research Categories: Biology, Molecular; Health Sciences, Radiology; Chemistry, Biochemistry

Abstract

Background: Src, an oncoprotein that drives progression of head and neck squamous cell carcinoma (HNSCC), is commonly hyperactivated in this disease. Unfortunately, the clinical benefit of targeting Src is significantly dampened in HNSCC patients, because the cytotoxic effects of anti-Src therapy and tumor resistance to it are less predictable. Thus, understanding the mechanism of tumor resistance to Src inhibition and seeking a way to overcome it are warranted. Methods: Dual drug-loaded nanoparticles (NPs) were developed to co-deliver Src inhibitor saracatinib (AZD0530) and AKT inhibitor capivasertib (AZD5363) into the same population of tumor cells. An orthotopic tongue tumor model was generated to evaluate the in vivo therapeutic effects. Cell growth was determined by CellTiter-Glo® Luminescent Cell Viability Kit, colony formation, and 3D culture, and tumor growth was determined by bioluminescence and tumor size. The molecular changes induced by the treatments were assessed by Western blotting and immunohistochemistry. Results: Capivasertib inactivated the AKT-S6 signaling and re-sensitized saracatinib-resistant HNSCC cells to saracatinib. Combination of capivasertib with saracatinib suppressed HNSCC growth more efficiently than either drug alone. Cathepsin B-sensitive NPs for co-delivering saracatinib and capivasertib significantly improved the efficacy of tumor repression without increasing side effects, which were due to highly specific tumor-targeting drug delivery system and synergistic anticancer effects by co-inactivation of AKT and Src in HNSCC cells. Conclusions: Addition of AKT blockade improves anti-HNSCC efficacy of anti-Src therapy, and co-delivery of capivasertib and saracatinib by tumor-targeting NPs has the potential to achieve better treatment outcomes than the free drug combination.