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.

Keywords: Chemotherapeutic Resistance; DNA Damage; HuR; Hypoxia; Pancreatic Ductal Adenocarcinoma.

Figure 1

PDA resistance mechanisms. Both extrinsic factors (which include the role of surgery, tumor microenvironment, stroma, etc.) and intrinsic cellular factors (ranging from somatic mutations, transcriptional and post-transcriptional reprogramming) contribute significantly to acute and acquired resistance to the existing therapeutic approaches used for treating PDA.

Figure 2

PDA progression and treatment strategies. In the era of next generation sequencing and novel molecular diagnostics, the ability to use circulating tumor cells/DNA (and conventional biopsies) allows us to detect and map accumulated somatic mutations and molecular alterations which may be a result of disease progression or exposure to chemotherapy. (Abbreviations. MP- Molecular Profiling)

Figure 3

Combating PDA therapeutic resistance. Patients eligible for surgical resection can be further stratified to optimize treatment, gain maximal response after resection and improve prognosis by exploring neoadjuvant chemotherapy, anti-growth factor therapy, etc. to keep the tumor localized and prevent micrometastases. In the patients with metastatic disease, local or advanced, inhibiting the intrinsic pathways through combination 'targeted' strategies can improve response to current standard- of- care therapies. (Abbreviations. NGS- Next Generation Sequencing)