Abstract 4912: Anticancer activity of Hsp90 inhibitor AUY922 in nasopharyngeal carcinoma and non-small cell lung cancer cells

Abstract

Abstract Introduction: Nasopharyngeal carcinoma (NPC) and non-small cell lung cancer (NSCLC) are two of the most prevalent cancers in Southern China. Although cisplatin therapy may be initially successful, its effectiveness is often significantly reduced in patients with relapsed disease. There is an urgent need to overcome cisplatin resistance in the treatment of NPC and NSCLC. Luminespib (AUY922) is an experimental drug candidate for the treatment of cancer. It is an inhibitor of heat shock protein 90 (Hsp90), a chaperone protein that plays a role in modifying a variety of proteins involved in tumorigenesis. Hsp90 inhibitors have demonstrated potent activity in preclinical testing and clinical trials against various cancer types. We sought to investigate the preclinical efficacy of AUY922 and evaluate its anticancer effect in cisplatin-resistant NPC and NSCLC cells. Materials and Methods: Two NPC cells (HK1 and Hone1), four NSCLC cells (A549, SW900, NCI-H1975, and HCC4006), one normal lung cells (CCD11Lu), two cisplatin-resistant NPC cells (HK1-R and Hone1-R), and one cisplatin-resistant NSCLC cells (A549-R) were cultured and treated with 100 nM AUY922 for 48 hours. A cell proliferation assay was performed in triplicate to determine the antiproliferative effects of AUY922 on cancer cells. Flow cytometry was used for cell cycle analysis. The apoptotic cells were evaluated by Annexin V and Western blot analysis. Nude mice were used to test the effects of intraperitoneal injection of AUY922 on tumor growth. Results: We found that AUY922 significantly inhibited in vitro growth in all the two NPC (44% and 40%) and four NSCLC (53%, 77%, 50%, and 62%) cells in comparison to the normal lung cells (4%). The two cisplatin-resistant NPC cells (63% and 37%) also showed significant inhibition of viability after treatment with AUY922. However, there was only a slightly reduced viability in the cisplatin-resistant NSCLC cells (14%). Flow cytometry revealed that AUY922 induced G2/M and S phase arrest in HK1 and HK1-R cells. On the other hand, AUY922 also induced pro-apoptotic peaks in A549, A549-R, Hone1, and Hone1-R cells. Interestingly, Annexin V and Western blot analysis showed that cell death was not caused by apoptosis. In vivo, both AUY922 alone and the combination of AUY922 with cisplatin treatments inhibited NPC and NSCLC tumor growth without significant weight loss. In addition, the administration of AUY922 significantly reduced NPC and NSCLC tumor growth in the cisplatin-resistant mouse models. Conclusion: AUY922 exhibits potent anticancer activities in vitro and in vivo. These findings provide evidence that AUY922 could be useful for the treatment of NPC and NSCLC as a single agent or in combination with cisplatin. Most importantly, our results provide a preclinical proof of concept for the efficacy of AUY922 in cisplatin-resistant NPC and NSCLC treatment. Citation Format: William C. Cho, Chi F. Wong. Anticancer activity of Hsp90 inhibitor AUY922 in nasopharyngeal carcinoma and non-small cell lung cancer cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4912.