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

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.

Keywords: SRC family kinases; desmoplasia; drug discovery; fibrosis; kinase therapy; pancreatic cancer; transcription factors.

Figure 1

Simplified signaling pathways for kinases of interest in PDAC. Lipid bilayer represents cellular membrane; dashed line represents nuclear membrane; blue ovals represent kinases of interest; gray ovals represent other proteins; yellow circles represent phosphorylation; green circles represent downstream tumor suppression; red circles represent downstream oncogenicity or tumor promotion.

Figure 2

Kinase tissue distributions. The Genotype-Tissue Expression (GTEx) database was queried for all kinases of interest including 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)). Average median transcripts per million (TPM) were calculated for adipose, brain, cervix, colon, esophagus, heart, and skin subcategories. Asterisks (*) indicate key data relating to pancreatic ductal adenocarcinoma (PDAC). Samples collected from nondiseased tissue.