Targeting super-enhancer-associated oncogenes in oesophageal squamous cell carcinoma

Abstract

Objectives Oesophageal squamous cell carcinoma (OSCC) is an aggressive malignancy and the major histological subtype of oesophageal cancer. Although recent large-scale genomic analysis has improved the description of the genetic abnormalities of OSCC, few targetable genomic lesions have been identified, and no molecular therapy is available. This study aims to identify druggable candidates in this tumour. Design High-throughput small-molecule inhibitor screening was performed to identify potent anti-OSCC compounds. Whole-transcriptome sequencing (RNA-Seq) and chromatin immunoprecipitation sequencing (ChIP-Seq) were conducted to decipher the mechanisms of action of CDK7 inhibition in OSCC. A variety of in vitro and in vivo cellular assays were performed to determine the effects of candidate genes on OSCC malignant phenotypes. Results The unbiased high-throughput small-molecule inhibitor screening led us to discover a highly potent anti-OSCC compound, THZ1, a specific CDK7 inhibitor. RNA-Seq revealed that low-dose THZ1 treatment caused selective inhibition of a number of oncogenic transcripts. Notably, further characterisation of the genomic features of these THZ1-sensitive transcripts demonstrated that they were frequently associated with super-enhancer (SE). Moreover, SE analysis alone uncovered many OSCC lineage-specific master regulators. Finally, integrative analysis of both THZ1-sensitive and SE-associated transcripts identified a number of novel OSCC oncogenes, including PAK4, RUNX1, DNAJB1, SREBF2 and YAP1, with PAK4 being a potential druggable kinase. Conclusions Our integrative approaches led to a catalogue of SE-associated master regulators and oncogenic transcripts, which may significantly promote both the understanding of OSCC biology and the development of more innovative therapies.

Novel p21-Activated Kinase 4 (PAK4) Allosteric Modulators Overcome Drug Resistance and Stemness in Pancreatic Ductal Adenocarcinoma

“…Instead these PAK4 allosteric modulators (PAMs) effect steady state phosphorylation and total PAK4 levels in cancer cells. The interaction with PAK4 was first discovered using SILAC and a resin tagged compound, KPT-7523, as described in Materials and Methods (14, 17). Figure 1A shows the structure of PAM analogues investigated in this study.…”

Genomic and Epigenomic Aberrations in Esophageal Squamous Cell Carcinoma and Implications for Patients

“…66 Super-enhancers promote transcriptional activation of oncogenes in ESCC cells and squamous lineage-specific genes. 67 It is not clear how alterations of chromatin modification contribute to development of ESCCs. Nonetheless, researchers have begun to investigate the antineoplastic effects of inhibiting the activities of HDAC, 68 CDK7, 67 and LSD1 69 in ESCC cells.…”

Anticystogenic activity of a small molecule PAK4 inhibitor may be a novel treatment for autosomal dominant polycystic kidney disease

“…1a) that shows dual inhibition of PAK4 and NAMPT 9,15,17,18 . When injected into rats, the compound and its acetylated metabolite were found by LC-MS analysis to be present in plasma and bile but undetectable in urine (unpublished observations).…”

“…In this report we investigate the utility of the dual PAK4/NAMPT inhibitor, KPT-9274, (and by inference analogs such as KPT-7523, KPT-8752, and KPT-9331) 14,15 to reduce PAK4 steady state protein levels in PKD. We show here that KPT-9274 treatment, primarily through PAK4 inhibition, causes reduction of cell proliferation and induction of apoptosis in PKD.…”