Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive, metastatic disease with limited treatment options. Factors contributing to the metastatic predisposition and therapy resistance in pancreatic cancer are not well understood. Here, we used a mouse model of KRAS-driven pancreatic carcinogenesis to define distinct subtypes of PDAC metastasis: epithelial, mesenchymal and quasi-mesenchymal. We examined pro-survival signals in these cells and the therapeutic response differences between them. Our data indicate that the initiation and maintenance of the transformed state are separable, and that KRAS dependency is not a fundamental constant of KRAS-initiated tumors. Moreover, some cancer cells can shuttle between the KRAS dependent (drug-sensitive) and independent (drug-tolerant) states and thus escape extinction. We further demonstrate that inhibition of KRAS signaling alone via co-targeting the MAPK and PI3K pathways fails to induce extensive tumor cell death and, therefore, has limited efficacy against PDAC. However, the addition of histone deacetylase (HDAC) inhibitors greatly improves outcomes, reduces the self-renewal of cancer cells, and blocks cancer metastasis in vivo. Our results suggest that targeting HDACs in combination with KRAS or its effector pathways provides an effective strategy for the treatment of PDAC.
Highlights
Pancreatic ductal adenocarcinoma, the most common form of pancreatic cancer, is a highly aggressive disease characterized by an insidious onset and low survival rate
The majority of tumors derived from SCA1- cells showed features of undifferentiated carcinoma, whereas the histology of tumors derived from SCA1+ cells exhibited a pattern of well-differentiated adenocarcinoma (Fig. S1)
The mutated KRAS oncogene is found in approximately 90% of cases of Pancreatic ductal adenocarcinoma (PDAC), and generally in about 30% of human cancers [34]
Summary
Pancreatic ductal adenocarcinoma, the most common form of pancreatic cancer, is a highly aggressive disease characterized by an insidious onset and low survival rate. About 80% of patients with PDAC present with locally advanced or metastatic disease [1, 2]. The two main obstacles in the treatment of PDAC are late diagnosis and therapy resistance of the tumor. The efficacy of therapies in metastatic cancer is further limited by frequent acquisition of multidrug resistance. Most patients with metastatic pancreatic cancer are considered incurable and rarely survive more than one year [1, 2]. The origins of pancreatic cancer, the feasibility of early detection, and the identity of genes and pathways responsible for the acquisition of malignant (metastatic) phenotype have yet to be determined
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