Integration of Bioinformatics Resources Reveals the Therapeutic Benefits of Gemcitabine and Cell Cycle Intervention in SMAD4-Deleted Pancreatic Ductal Adenocarcinoma.

Yao-Yu Hsieh,Pei-Ming Yang,Chia-Jung Chou,Tsang-Pai Liu,Kuen-Haur Lee,Hsin-Yi Chen

doi:10.3390/genes10100766

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the most common and aggressive type of pancreatic cancer. The five-year survival rate of PDAC is very low (less than 8%), which is associated with the late diagnosis, high metastatic potential, and resistance to therapeutic agents. The identification of better prognostic or therapeutic biomarker may have clinical benefits for PDAC treatment. SMAD4, a central mediator of transforming growth factor beta (TGFβ) signaling pathway, is considered a tumor suppressor gene. SMAD4 inactivation is frequently found in PDAC. However, its role in prognosis and therapeutics of PDAC is still unclear. In this study, we applied bioinformatics approaches, and integrated publicly available resources, to investigate the role of SMAD4 gene deletion in PDAC. We found that SMAD4 deletion was associated with poorer disease-free, but not overall, survival in PDAC patients. Cancer hallmark enrichment and pathway analysis suggested that the upregulation of cell cycle-related genes in SMAD4-deleted PDAC. Chemotherapy response profiling of PDAC cell lines and patient-derived organoids revealed that SMAD4-deleted PDAC was sensitive to gemcitabine, the first-line treatment for PDAC, and specific cell cycle-targeting drugs. Taken together, our study provides an insight into the prognostic and therapeutic roles of SMAD4 gene deletion in PDAC, and SMAD4 gene copy numbers may be used as a therapeutic biomarker for PDAC treatment.

Highlights

The incidence of pancreatic cancer has markedly increased over the past few years [1]
From the diagram of SMAD4 gene and the encoded protein, mutations occurred more frequently in the MAD homology 2 (MH2) domain that is responsible for heteromerization and transactivation (Figure 1c)
cyclin-dependent kinase 1 (CDK1), together with polo-like kinase 1 (PLK1), were required for mitotic entry [27]. These analyses suggest that active cell cycle progression is a major phenotype in SMAD4-deleted Pancreatic ductal adenocarcinoma (PDAC)

Summary

Introduction

The incidence of pancreatic cancer has markedly increased over the past few years [1]. Pancreatic ductal adenocarcinoma (PDAC), the most common and aggressive type of pancreatic cancer, accounts for more than 85% of cases [2]. The five-year survival rate of PDAC is less than 8% [1]. Such high lethality is largely correlated with late diagnosis, high metastatic potential, and resistance to therapeutic agents [3]. Even for patients with early-stage disease, the recurrent rate is still high [4]. Surgical resection remains the only potential curative treatment.

Methods

Results

Conclusion