Study of adaptive responses to drug treatments in pancreatic cancer cells

One of the most important and unsolved problems in the therapy of pancreatic tumors is the development of resistance to pharmacological treatments. Inefficacy of therapies leads to the progression of these cancers, worsening the quality of life and shortening the lifespan. Tumors that interest the pancreas are quite different from each other, depending on the cell type by which it origins and on the alterations of pancreatic functionality. They may be classified in two groups: endocrine tumors, which arise from pancreatic endocrine cells, and carcinomas, which derive from cells with exocrine functions. Cancers derived from these two groups are very different in terms of prognosis. Indeed, pancreatic endocrine tumors are defined as “indolent”, due to their slow rate of growth and to the long survival of patients in most of the cases. On the contrary, pancreatic ductal carcinoma is considered one of the most lethal tumors, due to the inefficacy of chemotherapeutic treatment and by the short survival of patient. In both cases, tumors are incurable in most patients. The pharmacological approaches used for the treatment of endocrine or ductal tumors are different: in endocrine tumors, which have a slow progression rate, inhibitors of cell growth are used in the majority of cases, while in ductal carcinomas, which have a faster progression, chemotherapy with agents that impair replication of cancerous cells is preferred. The aim of the work presented in this thesis was to investigate the mechanisms at the basis of drug resistance in pancreatic tumors. The first part of the work is focused on the study of endocrine tumors and it proposes a novel strategy to counteract the problem of resistance of pharmacological treatment with Everolimus, using in vitro models. The second part of the work concerns the investigation of the molecular features of pancreatic ductal cancer cells, and how these mechanisms may be involved in the malignity of cancer cells and in the acquisition of resistance to chemotherapy.