The dual kinase complex FAK-Src as a promising therapeutic target in cancer

Figures & data

Figure 1 FAK/Src complex mediated signaling pathway.

Notes: The FAK/Src complex transduces signals from a variety of membrane receptors such as tyrosine kinase repectors and integrins through the activation of intracellular signaling pathways such as PI3K-AKt and Ras-MAPK to reach a cellular response.
Abbreviations: ERK, extracellular signal regulated kinase; FA, focal adhesions; MEK, mitogen-activated protein; FAK, focal adhesion kinase; VEGF, vascular endothelial growth factor; MMPs, matrix metalloproteinases.

Figure 2 FAK and Src structure.

Notes: A) FAK structure. FAK harbors a central region with kinase activity that is flanked by a N-terminal region that contains the FERM domain and by a C-terminal region that contains the FAT domain. The autophosphorylation in its Y397 residue increases its catalytic kinase activity and allows the binding of specific intracellular proteins. FAK is phosphorylated by Src in its Y576 and Y577 residues allowing its full catalytic activity. In absence of stimulus, the FERM domain works as a negative regulator of FAK activity through its interaction with the kinase domain preventing the phosphorylation in Y397. In response of stimuli, the FERM domain interacts with the cytoplasmic tail of the integrins. Allowing the autophosphorylation of FAK in this tyrosine. The FAT domain, placed in the C-terminal region, mediates the co-localization of FAK with the FA areas through the interaction of FAK with the FA associated proteins talin and paxillin. Two proline-rich domains (PR) mediate the interaction of FAK with SH3 containing proteins such as p130 CAS. B) Src structure. Src is comprised of six domains: a SH4 involved in targeting Src to the plasmatic membrane, a region U that is specific of each Src family member, a SH3 and a SH2 domain involved in the interaction of Src with other intracellular proteins and a SH1 domain involved in ATP and substrate binding. The phosphorylation in Y419 residue of the SH1 domain is required for maximum kinase activity. Placed immediately adjacent to the SH1 domain there is a negative regulatory domain. After phosphorylation of the Y530 residue, in the negative regulatory domain, Src becomes inactive.

Abbreviations: FAK, focal adhesion protein; RTK, tyrosine kinase receptor; FERM, Band 4.1 Ezrin, Radixin, Moesin; PI3K, phosphoinositide 3 kinase.

Figure 3 Role of the FAK-Src complex in the malignant progression of solid tumors.

Notes: FAK and Src play a critical role in solid tumor progression mainly through its ability to promote the epithelial-mesenchymal transition associated with the metastatic behavior of solid tumors.
Abbreviations: ECM, extracellular matrix; EMT, epithelial mesenchynal transitions; FAK, focal adhesion kinase; Src, steroid receptor coactivator.

Table 1 Summary of FAK and Src inhibitors under clinical and preclinical development

Drug	Target (IC50)	IC50	IC50	IC50	Preclinical activity	Clinical activity
	Src	FAK	AbI	IGFIR
BMS-354825 (Dasatinib)	0.55 nM		3.0 nM		Solid and hematological tumor models	Approved in Imatinib refractory CML and Philadelphia chromosome + ALL, Phase 1–2 clinical trials in solid and hematological tumors are underway
PF-562,271	797 nM	1.5 nM (0.7 ng/mL)		>500 nM	Colon, breast, prostate, pancreatic and lung tumor models	Phase 1 clinical trial in solid tumors has been already communicated
TAE-226		100 nM/L = 100 nM		300 nM/L = 300 nM	Glioma and human pancreatic tumor cell lines	Not yet
AZD0530	≤4 nM 27 nM				Skin, prostate, breast and pancreatic tumor models	Phase 1–2 clinical trial underway
SKI-606 (Bosutinib)	3.8 nM				CML, colon and breast models	Phase 1 clinical trial has been already communicated, Ph II clinical trial in CML patients after imatinib failure under development

Abbreviations: FAK, focal adhesion kinase; CML, chronic myelogenous leukemia; IGF, insulin-like growth factor; IC, inhibitory concentration.