Emerging Kinase Therapeutic Targets in Pancreatic Ductal Adenocarcinoma and Pancreatic Cancer Desmoplasia.

Justin F Creeden,F Charles Brunicardi,Ali S Imami,Robert E Mccullumsmith,Rammohan Shukla,Faris Naji,Tushar Tomar,Shi-He Liu,Khaled Alganem,Nicholas D Henkel

doi:10.3390/ijms21228823

Abstract

Kinase drug discovery represents an active area of therapeutic research, with previous pharmaceutical success improving patient outcomes across a wide variety of human diseases. In pancreatic ductal adenocarcinoma (PDAC), innovative pharmaceutical strategies such as kinase targeting have been unable to appreciably increase patient survival. This may be due, in part, to unchecked desmoplastic reactions to pancreatic tumors. Desmoplastic stroma enhances tumor development and progression while simultaneously restricting drug delivery to the tumor cells it protects. Emerging evidence indicates that many of the pathologic fibrotic processes directly or indirectly supporting desmoplasia may be driven by targetable protein tyrosine kinases such as Fyn-related kinase (FRK); B lymphoid kinase (BLK); hemopoietic cell kinase (HCK); ABL proto-oncogene 2 kinase (ABL2); discoidin domain receptor 1 kinase (DDR1); Lck/Yes-related novel kinase (LYN); ephrin receptor A8 kinase (EPHA8); FYN proto-oncogene kinase (FYN); lymphocyte cell-specific kinase (LCK); tec protein kinase (TEC). Herein, we review literature related to these kinases and posit signaling networks, mechanisms, and biochemical relationships by which this group may contribute to PDAC tumor growth and desmoplasia.

Highlights

Pancreatic endocrine tissue contains distinct populations of hormone-producing pancreatic islet cells
Our identification and contextualization (Tables 1 and 2) of 10 kinases identified as candidate or lead candidate kinases responsible for the differential phosphorylation signatures observed between commercial and patient-derived pancreatic ductal adenocarcinomas (PDAC) cell lines compared to wild-type pancreatic patient samples encourages further study of the unique relationship between pancreatic tumor cells and the desmoplastic stromal environments that support tumor progression and present significant obstacles to pancreatic cancer treatment
Combining emerging evidence with previously published findings, we suggest a mechanism for the relationship between B lymphoid kinase (BLK), the Pancreatic and Duodenal Homeobox 1 (PDX1) transcription factor, and pancreatic disease

Summary

Introduction

Pancreatic endocrine tissue contains distinct populations of hormone-producing pancreatic islet cells. Another signaling node of LYN in pancreatic cancer involves the megakaryocyteassociated tyrosine kinase (MATK) (Figure 1) This kinase is overexpressed in breast cancer patient samples and demonstrates tumor suppressive properties, inhibiting cancer cell growth and proliferation [153]. Knowledge of the role that LCK plays in solid human tumors is developing, with reports that LCK is expressed in human breast cancer specimens [213]; LCK is overexpressed and activated in lung cancer cell lines [214]; LCK is upregulated in bile duct cancer cells and associates with early tumor recurrence [215]; LCK inhibition in human glioma cells decreases malignant progression [216]. Expression appears to be a positive prognostic marker; demonstrates potential as early diagnosis biomarker

12. Tyrosine Kinase Inhibitors

Findings

13. Conclusions