Abstract 4951: Proteasome inhibitor carfilzomib induces apoptosis via downregulation of AKT pathway in HPV negative HNSCC

Abstract

Abstract Background Head and neck squamous cell carcinoma (HNSCC) presents in heterogenous sites, varied etiology and risk factors, and has diverse genetic background which confer dissimilar response to treatments, including chemotherapy. Here we tested the hypothesis that investigation of HPV presence in a HNSCC cell line would identify pathway contributing to oncogenesis of other HNSCC. We sought to identify pathways that differentially affect HNSCC according to the genetic background, therefore identifying targets and suitable candidate for treatment. We used genetic and pharmacological approaches to inhibit AKT pathway in HNSCC cell lines. Materials & methods Chemical genetic library screening against 6 HNSCC cell lines were performed. The high throughput combinatorial small molecule screening for cell viability and apoptosis was carried out. Candidate agents were validated in both CAL-27 (HPV-negative) and UM-SCC-47 (HPV-positive) cell lines. Identified pathways and representative targeted agents were validated in vitro. Expression of related protein were confirmed by western blot assay. Results EGFR, PIK3CA, mTOR, CDK1, HSP90AB1, HDAC1, and PSMD1 pathways were identified to be susceptible pathways in HNSCC using high throughput chemical genetic library screening. In vitro validation of carfilzomib showed IC50 of 7.07nM in CAL-27 cells and IC50 of 26.3nM in UM-SCC-47 cells. Knockdown of PSMD1 transcripts by transfected siRNAs reduced CAL-27 cells viability. Carfilzomib regulates the AKT pathway by decreasing t-AKT, p-AKT, p-ERK, p-S6 proteins and increasing p21 in CAL-27. Conclusion Inhibition of AKT pathway treatment with proteasome inhibitor carfilzomib is effective in HPV-negative HNSCC cells. Taken together, our findings reveal carfilzomib induced the apoptotic pathway and suggest that carfilzomib, the representative of a new class of chemotherapeutic drug, may be utilized for overcoming cisplatin-resistance in human SCC. Citation Format: Woo-Jin Jeong, Jiyeong Kim, Hye-Yeon Lee, Zhiyong Wang, Walt Amornphimoltham, Silvio Gutkind. Proteasome inhibitor carfilzomib induces apoptosis via downregulation of AKT pathway in HPV negative HNSCC. [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 4951.