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

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2020 Nov 25

PMID 33233470

Citations 11

Authors

Justin F Creeden

Khaled Alganem

Ali S Imami

Nicholas D Henkel

F Charles Brunicardi

Shi-He Liu

Rammohan Shukla

Tushar Tomar

Faris Naji

Robert E McCullumsmith

Affiliations

Soon will be listed here.

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.

Citing Articles

Tumor-Intrinsic Kinome Landscape of Pancreatic Cancer Reveals New Therapeutic Approaches.

Xu Y, Peng X, East M, McCabe I, Stroman G, Jenner M Cancer Discov. 2024; 15(2):346-362.

PMID: 39632628 PMC: 11805639. DOI: 10.1158/2159-8290.CD-23-1480.

Lck Function and Modulation: Immune Cytotoxic Response and Tumor Treatment More Than a Simple Event.

De Sanctis J, Garmendia J, Duchova H, Valentini V, Puskasu A, Kubickova A Cancers (Basel). 2024; 16(15).

PMID: 39123358 PMC: 11311849. DOI: 10.3390/cancers16152630.

The molecular mechanism underlying KRAS regulation on STK31 expression in pancreatic ductal adenocarcinoma.

Liu Y, Tang S, Li C, To K, Li B, Chan S Cancer Sci. 2024; 115(10):3288-3304.

PMID: 39054797 PMC: 11447899. DOI: 10.1111/cas.16286.

Targeting miRNA and using miRNA as potential therapeutic options to bypass resistance in pancreatic ductal adenocarcinoma.

Vahabi M, Dehni B, Antomas I, Giovannetti E, Peters G Cancer Metastasis Rev. 2023; 42(3):725-740.

PMID: 37490255 PMC: 10584721. DOI: 10.1007/s10555-023-10127-w.

Paired protein kinases PRKCI-RIPK2 promote pancreatic cancer growth and metastasis via enhancing NF-κB/JNK/ERK phosphorylation.

Jiao J, Ruan L, Cheng C, Wang F, Yang P, Chen Z Mol Med. 2023; 29(1):47.

PMID: 37016317 PMC: 10074657. DOI: 10.1186/s10020-023-00648-z.

References

Hua L, Zhu M, Song X, Wang J, Fang Z, Zhang C . FRK suppresses the proliferation of human glioma cells by inhibiting cyclin D1 nuclear accumulation. J Neurooncol. 2014; 119(1):49-58. DOI: 10.1007/s11060-014-1461-y. View

Britton D, Zen Y, Quaglia A, Selzer S, Mitra V, LoBner C . Quantification of pancreatic cancer proteome and phosphorylome: indicates molecular events likely contributing to cancer and activity of drug targets. PLoS One. 2014; 9(3):e90948. PMC: 3966770. DOI: 10.1371/journal.pone.0090948. View

Duarte-Medrano G, Lopez-Mendez I, Ramirez-Luna M, Valdovinos-Andraca F, Cruz-Martinez R, Medina-Vera I . Analysis of circulating blood and tissue biopsy PDX1 and MSX2 gene expression in patients with pancreatic cancer: A case-control experimental study. Medicine (Baltimore). 2019; 98(26):e15954. PMC: 6616340. DOI: 10.1097/MD.0000000000015954. View

Okada J, Yamada E, Saito T, Yokoo H, Osaki A, Shimoda Y . Dapagliflozin Inhibits Cell Adhesion to Collagen I and IV and Increases Ectodomain Proteolytic Cleavage of DDR1 by Increasing ADAM10 Activity. Molecules. 2020; 25(3). PMC: 7038111. DOI: 10.3390/molecules25030495. View

Humbert M, Casteran N, Letard S, Hanssens K, Iovanna J, Finetti P . Masitinib combined with standard gemcitabine chemotherapy: in vitro and in vivo studies in human pancreatic tumour cell lines and ectopic mouse model. PLoS One. 2010; 5(3):e9430. PMC: 2832006. DOI: 10.1371/journal.pone.0009430. View

Calautti E, Grossi M, Mammucari C, Aoyama Y, Pirro M, Ono Y . Fyn tyrosine kinase is a downstream mediator of Rho/PRK2 function in keratinocyte cell-cell adhesion. J Cell Biol. 2002; 156(1):137-48. PMC: 2173591. DOI: 10.1083/jcb.200105140. View

Lofdahl A, Rydell-Tormanen K, Muller C, Martina Holst C, Thiman L, Ekstrom G . 5-HT2B receptor antagonists attenuate myofibroblast differentiation and subsequent fibrotic responses in vitro and in vivo. Physiol Rep. 2016; 4(15). PMC: 4985542. DOI: 10.14814/phy2.12873. View

Jin L, Craven R . The Rak/Frk tyrosine kinase associates with and internalizes the epidermal growth factor receptor. Oncogene. 2013; 33(3):326-35. DOI: 10.1038/onc.2012.589. View

Sulman E, Tang X, Allen C, Biegel J, Pleasure D, Brodeur G . ECK, a human EPH-related gene, maps to 1p36.1, a common region of alteration in human cancers. Genomics. 1997; 40(2):371-4. DOI: 10.1006/geno.1996.4569. View

10.

Zepecki J, Snyder K, Moreno M, Fajardo E, Fiser A, Ness J . Regulation of human glioma cell migration, tumor growth, and stemness gene expression using a Lck targeted inhibitor. Oncogene. 2018; 38(10):1734-1750. PMC: 6462869. DOI: 10.1038/s41388-018-0546-z. View

11.

Lun X, Szklarczyk D, Gabor A, Dobberstein N, Zanotelli V, Saez-Rodriguez J . Analysis of the Human Kinome and Phosphatome by Mass Cytometry Reveals Overexpression-Induced Effects on Cancer-Related Signaling. Mol Cell. 2019; 74(5):1086-1102.e5. PMC: 6561723. DOI: 10.1016/j.molcel.2019.04.021. View

12.

Felices M, Falk M, Kosaka Y, Berg L . Tec kinases in T cell and mast cell signaling. Adv Immunol. 2007; 93:145-84. DOI: 10.1016/S0065-2776(06)93004-1. View

13.

Malek S, Dordai D, Reim J, DINTZIS H, Desiderio S . Malignant transformation of early lymphoid progenitors in mice expressing an activated Blk tyrosine kinase. Proc Natl Acad Sci U S A. 1998; 95(13):7351-6. PMC: 22613. DOI: 10.1073/pnas.95.13.7351. View

14.

Hamasaki Y, Doi K, Maeda-Mamiya R, Ogasawara E, Katagiri D, Tanaka T . A 5-hydroxytryptamine receptor antagonist, sarpogrelate, reduces renal tubulointerstitial fibrosis by suppressing PAI-1. Am J Physiol Renal Physiol. 2013; 305(12):F1796-803. DOI: 10.1152/ajprenal.00151.2013. View

15.

Bose S, Le A . Glucose Metabolism in Cancer. Adv Exp Med Biol. 2018; 1063:3-12. DOI: 10.1007/978-3-319-77736-8_1. View

16.

Je D, O Y, Ji Y, Cho Y, Lee D . The inhibition of SRC family kinase suppresses pancreatic cancer cell proliferation, migration, and invasion. Pancreas. 2014; 43(5):768-76. DOI: 10.1097/MPA.0000000000000103. View

17.

Melstrom L, Salazar M, Diamond D . The pancreatic cancer microenvironment: A true double agent. J Surg Oncol. 2017; 116(1):7-15. PMC: 5989710. DOI: 10.1002/jso.24643. View

18.

Sakurai Y, Kubota N, Takamoto I, Obata A, Iwamoto M, Hayashi T . Role of insulin receptor substrates in the progression of hepatocellular carcinoma. Sci Rep. 2017; 7(1):5387. PMC: 5511151. DOI: 10.1038/s41598-017-03299-3. View

19.

Rajagopal K, Sommers C, Decker D, Mitchell E, Korthauer U, Sperling A . RIBP, a novel Rlk/Txk- and itk-binding adaptor protein that regulates T cell activation. J Exp Med. 1999; 190(11):1657-68. PMC: 2195727. DOI: 10.1084/jem.190.11.1657. View

20.

Liu S, Hao X, Ouyang X, Dong X, Yang Y, Yu T . Tyrosine kinase LYN is an oncotarget in human cervical cancer: A quantitative proteomic based study. Oncotarget. 2016; 7(46):75468-75481. PMC: 5342753. DOI: 10.18632/oncotarget.12258. View