The Landscape of Pancreatic Cancer Therapeutic Resistance Mechanisms

Abstract

Pancreatic cancer (pancreatic ductal adenocarcinoma, PDA) is infamously moving to the top of the list as one of the most lethal cancers with an overall 5 year survival rate of 7%. Multiple genomic-based and molecular characterization studies of PDA specimens and established animal models have provided the field with multiple targets and a progression model of this disease. Still, to date, the best therapeutic options are surgery and combination cytotoxic therapies. In general, even in the best case scenario (i.e., an early stage diagnosis and a response to a specific therapy), most of these fortunate patients' PDA cells acquire or exert resistance mechanisms and eventually kill the patient. Herein, we touch on a growing field of investigation that focuses on PDA cell therapeutic resistance mechanisms. We examine extrinsic elements (i.e., the tumor microenvironment, hypoxia) to the intrinsic processes within the cell (i.e., post-transcriptional gene regulation and somatic mutations) that are important for therapeutic efficacy and resistance. Even as better targeted and personalized approaches move through the clinical trial pipeline the discussed resistance mechanisms will most likely play a role in the management of this deadly disease.

An Overview of Genetic Changes and Risk of Pancreatic Ductal Adenocarcinoma

“…Nearly 10% of PDAC patients are carriers of mutation of BRCA1, BRCA2, PALB and other genes engaged in DNA repair 2. Analysis of sporadic and familial PC individuals showed almost 40% increased risk of cancer when there is PRSS1 mutation and long-standing hereditary pancreatitis.…”

“…The survival rate, with this extremely aggressive cancer, is drastically reduced from 25% of 1-year survival to below 5% in 5-year. Up to recognized a pancreatic cancer only 15-20% of patients are resectable 1,2. In this group mortality and morbidity rates are reduced to almost 40% of 5-year survival 3.…”

“…Due to the sequence of certain events during pancreatic carcinogenesis its progression is referred to as early (with KRAS mutation and shortening of telomeres), intermediate (associated with inactivation of CDKN2A2 gene by mutations or epigenetic mechanisms) and late (connected with “switching off” mutations of p53 and SMAD4 genes) 2.…”

CRISPR Knockout of the HuR Gene Causes a Xenograft Lethal Phenotype

“…HuR is abundant in both PDA and CRC specimens compared to normal adjacent tissue with cytoplasmic subcellular localization associated with increased tumor stage (12,13). As tumor cells are under stress in the tumor microenvironment (14) (e.g., nutrient deprivation and hypoxia) (15,16), HuR translocates from the nucleus, binds to pro-oncogenic mRNA transcripts (e.g. WEE1, PIM1, COX-2, VEGF ), promoting cancer cell survival and tumorigenesis (14,17,18).…”

“Heat shock protein 70 in pancreatic diseases: Friend or foe”

“…Chemotherapy in pancreatic cancer is fraught with one significant problem, the acquisition of resistance to an initially susceptible drug. Drug resistance leads to recurrence and advancing disease in almost all pancreatic cancer patients treated with systemic chemotherapy . In this scenario, Minnelide may provide an important advantage in overcoming this challenge .…”