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Review
. 2016;20(3):341-59.
doi: 10.1517/14728222.2016.1094057. Epub 2015 Oct 6.

Molecular signature of pancreatic adenocarcinoma: an insight from genotype to phenotype and challenges for targeted therapy

Ibrahim H Sahin  1 , Christine A Iacobuzio-Donahue  2 , Eileen M O'Reilly  2   3
Affiliations
Review

Molecular signature of pancreatic adenocarcinoma: an insight from genotype to phenotype and challenges for targeted therapy

Ibrahim H Sahin et al. Expert Opin Ther Targets. 2016.

Abstract

Introduction: Pancreatic adenocarcinoma remains one of the most clinically challenging cancers despite an in-depth characterization of the molecular underpinnings and biology of this disease. Recent whole-genome-wide studies have elucidated the diverse and complex genetic alterations which generate a unique oncogenic signature for an individual pancreatic cancer patient and which may explain diverse disease behavior in a clinical setting.

Areas covered: In this review article, we discuss the key oncogenic pathways of pancreatic cancer including RAS-MAPK, PI3KCA and TGF-β signaling, as well as the impact of these pathways on the disease behavior and their potential targetability. The role of tumor suppressors particularly BRCA1 and BRCA2 genes and their role in pancreatic cancer treatment are elaborated upon. We further review recent genomic studies and their impact on future pancreatic cancer treatment.

Expert opinion: Targeted therapies inhibiting pro-survival pathways have limited impact on pancreatic cancer outcomes. Activation of pro-apoptotic pathways along with suppression of cancer-stem-related pathways may reverse treatment resistance in pancreatic cancer. While targeted therapy or a 'precision medicine' approach in pancreatic adenocarcinoma remains an elusive challenge for the majority of patients, there is a real sense of optimism that the strides made in understanding the molecular underpinnings of this disease will translate into improved outcomes.

Keywords: K-Ras pathway; Wnt signaling; cancer stem cells; expression signature; molecular pathways; notch signaling; p53; pancreatic cancer; targeted treatment.

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Figures

Figure 1
Figure 1. Core oncogenic pathways in pancreatic cancer cells
Activation of diverse pro-survival pathways such as MAPK, PIK3CA-m-TOR and TGF-β in setting of mutant p53 and p16. EMT: Epithelialmesenchymal transition; ERK: Extracellular signal regulated kinase pathway; JNK: Jun N-terminal kinase; PTEN: Phosphotase tensin homolog; PKA: Protein kinase A.
Figure 2
Figure 2. Model progression of pancreatic cancer
Multistep activation of growth pathways from clonal expansion to gain of stemness properties; model progression of pancreatic cancer. EMT: Epithelialmesenchymal transition.
Figure 3
Figure 3. Possible resistance mechanisms
Rebound activation of PI3KCA and K-Ras pathways along with increased RTKs and anti-apoptotic proteins upon treatment with MEK and m-TOR inhibitors. ERK: Extracellular signal regulated kinase pathway.
Figure 4
Figure 4. Models of premalignant lesion
Model for development of IPMN and PanIN. Progression for both is not mutually exclusive and both lesions may progress into pancreatic mucinous adenocarcinoma and pancreatic ductal adenocarcinoma (red arrows). IPMN: Intraductal papillary mucinous neoplasms; PanIN: Pancreatic intraepithelial lesions.
Figure 5
Figure 5. Oncogenic pathways in cancer stem cells
Activation of Sonic Hedgehog, Wnt and Notch pathways confers stemness properties and induce treatment resistance and metastasis.
See this image and copyright information in PMC

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