Abstract 4754: Targeted inhibition of the HNF1A/SHH axis by triptolide overcomes paclitaxel resistance in non-small cell lung cancer

Abstract Paclitaxel resistance is commonly associated with a poor prognosis in non-small cell lung cancer (NSCLC) patients, and there are no promising pharmacological treatments for paclitaxel resistance. Here, we constructed human NSCLC-derived paclitaxel-resistant cell lines as an effective tool to explore the mechanisms of chemoresistance. We discovered that triptolide, a monomer compound extracted from Tripterygium wilfordii Hook F, was able to reverse paclitaxel resistance by reducing ABCB1 expression in vivo and in vitro. Through high-throughput sequencing, we found that the SHH-initiated Hedgehog signaling pathway played an important role in this process. More importantly, triptolide could directly target HNF1A, a transcription factor of SHH, and inhibited HNF1A/SHH expression, ensuing in attenuation of Hedgehog signaling. Clinically, we found a positive correlation between HNF1A and SHH expression in both NSCLC tumor tissue microarrays and cancer network databases. These findings illuminated a novel molecular mechanism through which triptolide effectively targets and inhibits HNF1A, thereby impeding the activation of the Hedgehog signaling pathway and reducing the expression of ABCB1. This finding indicated the potential clinical application of triptolide and provided promising prospects in targeting the HNF1A/SHH pathway as a therapeutic strategy for NSCLC patients with paclitaxel resistance. Citation Format: Peichao Li, ngbing Li, Lingxiao Yang, Lei Liu, Xiaogang Zhao. Targeted inhibition of the HNF1A/SHH axis by triptolide overcomes paclitaxel resistance in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4754.