Department of Neurosciences, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA.
Department of Cancer Biology, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA.
Int J Mol Sci. 2020 Nov 21;21(22):8823. doi: 10.3390/ijms21228823.
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.
激酶药物发现是治疗研究的活跃领域，以前药物方面的成功改善了各种人类疾病患者的预后。在胰腺导管腺癌 (PDAC) 中，激酶靶向等创新药物策略未能显著提高患者的生存率。这可能部分归因于对胰腺肿瘤的不受控制的纤维增生反应。纤维增生基质增强了肿瘤的发展和进展，同时限制了药物递送到它所保护的肿瘤细胞。新出现的证据表明，许多直接或间接支持纤维增生的病理性纤维化过程可能是由可靶向的蛋白酪氨酸激酶驱动的，如 Fyn 相关激酶 (FRK)；B 淋巴样激酶 (BLK)；造血细胞激酶 (HCK)；ABL 原癌基因 2 激酶 (ABL2)；盘状结构域受体 1 激酶 (DDR1)；Lck/Yes 相关新型激酶 (LYN)；表皮生长因子受体 A8 激酶 (EPHA8)；FYN 原癌基因激酶 (FYN)；淋巴细胞特异性激酶 (LCK)；Tec 蛋白激酶 (TEC)。本文综述了与这些激酶相关的文献，并提出了信号网络、机制和生化关系，这些可能有助于 PDAC 肿瘤生长和纤维增生。
