Paclitaxel and triptolide impair MYC-driven cell cycle via suppressing chromatin reprogramming in ALDH1A3^High...

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy characterized by transcriptional heterogeneity and chemoresistance. We previously identified an aggressive PDAC subtype defined by high expression of aldehyde dehydrogenase 1 family member A3 (ALDH1A3), which sustained a basal-like transcriptional program through AP-1-dependent enhancer remodeling. However, effective therapeutic strategies for ALDH1A3^High PDAC remain undefined. This study aimed to identify subtype-specific therapeutic vulnerabilities, and define their chromatin-based mechanisms.

Public datasets, patient-derived cell cultures, and in vivo xenograft models were utilized to evaluate targeted drug effects, while associated chromatin regulatory mechanisms were interrogated using an integrative multi-omics framework combining RNA-seq, ATAC-seq, and functional assays.

Based on drug screening system, paclitaxel and triptolide effectively suppressed the ALDH1A3-associated transcriptional network, producing robust antitumor activity and significantly prolonging survival in ALDH1A3^High models. Further integrated RNA-seq and ATAC-seq analyses revealed that paclitaxel and triptolide converge on AP-1-dependent enhancer regulation, inducing widespread chromatin closure at distal regulatory elements and leading to the coordinated downregulation of MYC and its dimerization partner MAX. Functionally, MYC inhibition mimicked the effects of paclitaxel and triptolide, reproducing the suppression of E2F3 and subsequent cell-cycle arrest.

The paclitaxel-triptolide combination represented a rational therapeutic strategy that disrupted lineage-specific chromatin states and might offer a clinically relevant approach for improving outcomes in ALDH1A3^High PDAC patients.