Kinase signaling pathways as targets for intervention in pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer related mortality in the United States. The prognosis of patients with PDAC is extremely poor with a median survival of 6 months, in part due to the advanced stage at the time of diagnosis and early metastatic spread. A considerable body of evidence points to the involvement of the tyrosine kinase and serine/threonine kinase pathways as major effectors in pancreatic cancer development and as potential targets for intervention. These pathways regulate multiple cellular processes including cell growth, proliferation, migration, invasion and resistance to apoptosis. The relatively recent introduction of novel therapies targeting tyrosine kinase and serine/threonine kinase pathways have yielded dramatic results in certain hematological malignancies, and have resulted in significant advances in our ability to treat patients with melanoma, breast, lung and colon cancer, thereby leading to improved survival and quality of life. Unfortunately, similar therapeutic improvements have not occurred in PDAC. Thus, despite encouraging phase I/II studies, the vast majority of phase-III studies have failed to demonstrate improved efficacy in PDAC. This review will provide an overview on the different kinase signaling pathways in PDAC and the supporting data on targeted therapies available from pre-clinical and clinical studies.

Pancreatic cancer–associated retinoblastoma 1 dysfunction enables TGF-β to promote proliferation

“…We therefore performed gene set enrichment analysis (GSEA) of array data, which revealed that compared with KC cells, genes upregulated in KRC cells correlated strongly with activated TGF-β and TGF-β/Wnt signaling ( Figure 6, A and B). Wnt pathway activation was evidenced by elevated expression of Wnt7b and Wnt receptors Fzd2, 3,6, and 9 compared with their expression in KC cells (Supplemental Figure 7). Importantly, KRC cells expressed active β-catenin that was devoid of phosphates at GSK3β-targeted residues and of inactive (phosphorylated) GSK3β (p-GSK3β), and the levels of p-GSK3β were increased by TGF-β1 ( Figure 6C).…”

“…First, based on loss of the CDKN2A gene, the RB/p16 pathway was reported to be inactive in 98% of PDAC cases (42). Second, the presence of oncogenic KRAS in 95% of PDACs (24), occurring in conjunction with the overexpression of mitogenic tyrosine kinase receptors and their ligands (6), could combine to induce RB phosphorylation and inactivation. Third, 50% of PDAC cases overexpress Smad7, which suppresses TGF-β1-mediated growth inhibition by maintaining RB in a hyperphosphorylated state (23).…”

“…PDACs harbor major driver mutations in the KRAS oncogene (95%) and SMAD4 (55%), TP53 (70%), and CDKN2A (90%) tumor suppressor genes, the latter also being susceptible to epigenetic silencing (3,5). In addition, there is overexpression of tyrosine kinase receptors and ligands (6), constitutive activation of prosurvival pathways, including AKT and NF-κB (7,8), reactivation of developmental pathways, such as WNT and Notch (8,9), and overexpression of transforming growth factor β (TGF-β) isoforms (10). TGF-β overexpression is associated with early recurrence following resection and decreased survival (10), and suppression of TGF-β actions in immune-deficient orthotopic mouse models of PDAC attenuates tumor growth and metastasis (11,12).…”

“…PanIN are an important feature of PDAC initiation in both humans and GEMs, and PanIN progression to mPDAC is accelerated by deletion of the p53 (16), p16 Ink4a /p19 Arf (Cdkn2a) (17), Smad4 (15), p16 Ink4a (19), and RB (18) tumor suppressors. However, the RB1 gene is rarely mutated in hPDAC (20), and given the high frequency of KRAS and CDKN2A mutations occurring in conjunction with the overexpression of multiple tyrosine kinase receptors and increased cyclin D1 levels (6), the loss of RB function in PDAC presumably does not drive its pathobiology.…”

Gene Expression Profiling of Pancreatic Cancer Reveals a Significant Deregulation of the TGF-β Pathway and the Discovery of Genes for Prognosis

“…Although the survival benefit for the combination of the EGFR tyrosine-kinase-inhibitor erlotinib and gemcitabine was significant compared to gemcitabine monotherapy, this regime leads only to an *Address correspondence to this author at the Charité Medical University Berlin, Institute of Biochemistry, Charitéplatz 1 / Sitz: Virchowweg 6, 10117 Berlin, Germany; Tel: +49 30 450 528087; Fax: +49 30 450 52945; E-mail: andreas.klein@charite.de improvement from 5.91 months to 6.24 months in the OS [7]. Up to today, clinical trials with targeted therapies failed to improve OS in PDAC [8]. For example, the humanized monoclonal antibody against vascular endothelial growth factor A (VEGFA), bevacizumab, did not change the overall survival when compared to gemcitabine and erlotinib [9].…”