Abstract
Despite modern therapeutic advances, the survival prospects of pancreatic cancer patients have remained poor. Besides being highly metastatic, pancreatic cancer is challenging to treat because it is caused by a heterogeneous array of somatic mutations that impact a variety of signaling pathways and cellular regulatory systems. Here we use publicly available transcriptomic, copy number alteration and mutation profiling datasets from pancreatic cancer patients together with data on disease outcomes to show that the three major pancreatic cancer subtypes each display distinctive aberrations in cell signaling and metabolic pathways. Importantly, patients afflicted with these different pancreatic cancer subtypes also exhibit distinctive survival profiles. Within these patients, we find that dysregulation of the phosphoinositide 3-kinase and mitogen-activated protein kinase pathways, and p53 mediated disruptions of cell cycle processes are apparently drivers of disease. Further, we identify for the first time the molecular perturbations of signalling networks that are likely the primary causes of oncogenesis in each of the three pancreatic cancer subtypes.
Highlights
Pancreatic cancer is the most lethal form of cancer
We found that the transcript levels of certain key glycolytic pathway enzymes varied between pancreatic ductal adenocarcinoma (PDAC) subtypes: these included the transcript levels of pyruvate kinase (PKM), lactate dehydrogenase (LDHA) and pyruvate dehydrogenase complex kinase-1 (PDK1) which were highest in classical PDAC (C-PDAC) tumours and lowest in ELPDAC tumours (Figure 3B)
We found that alterations in p53 and cell cycle checkpoint pathway genes were most apparent in C-PDAC tumours (Figure 5B and 5C), whereas alterations in specific mitogen-activated protein kinase (MAPK) and PI3K-Mammalian Target of Rapamycin (mTOR) pathway genes were more apparent in quasi-mesenchymal PDAC (QM-PDAC) tumours (Figure 5D and 5E)
Summary
Pancreatic cancer is the most lethal form of cancer. It has an extremely poor prognosis with less than 20% of patients surviving for more than one year following diagnosis [1, 2]. A significant challenge to achieving better treatment outcomes has been the heterogeneity of pancreatic cancers Underlying this heterogeneity is the vast array of somatic mutations that are acquired during oncogenesis, and the varied effects that these mutations have on cell signalling pathways [6, 7]. Recent analyses of genomic sequence datasets from patients with advanced disease have identified potential activating mutations, many of which occur in genes encoding proteins that might be suitable drug targets [1, 8] In this regard the discovery of mutation hot-spots in various signalling kinases has already prompted the development of highly selective kinase inhibitors that are capable of killing pancreatic cancer cells. Used in conjunction with kinase-inhibitors, novel drugs targeting these pathway components could yield pancreatic cancer therapies with longer lasting effectiveness
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