FAK (Focal adhesion kinase), a non-receptor tyrosine kinase, can regulate the cytoskeleton and is reported to have increased expression in a number of tumor types, including breast, colon and ovarian cancers. Defactinib is a selective FAK inhibitor which dose-dependently down-regulated pFAK (Tyr397) at concentration ranging in 10nM-10μM in taxane-sensitive HeyA8 cells and 0.1-10μM in taxane-resistant HeyA8-MDR cells. Co-incubation of 1μM Defactinib and paclitaxel could decrease the paclitaxel-induced expression of YB-1 and its phosphorylation at Ser102 site, which has a potential role in oncogenic and drug-resistance pathways, as well as restored the location of YB-1 to cytoplasm, in HeyA8-MDR cells. For AKT is required to phosphorylation and translocation of YB-1, the signaling of AKT pathway was also examined. The resulted show that Defactinib could downregulate p-YB-1 and its nuclear translocation in an AKT-dependent manner, as well as inhibit p-FAK-Y397 and p-AKT-S473 in taxane-resistant SKOV3 cells. This inhibition of YB-1 by Defactinib through FAK may downregulate the expression of CD44, a downstream target of YB-1 and a partial contributor to the PTX-resistant phenotype, in HeyA8-MDR cells. Combined therapy of paclitaxel with Defactinib >25 mg/kg orally twice a day resulted in greater reduction in tumor growth of PTX-resistant models, including HeyA8-MDR and SKOV3-TR xenografts[1].
作用机制
Defactinib is an ATP-competitive, reversible inhibitor of FAK.[2]
Defactinib/地法替尼 细胞实验
Cell Line
Concentration
Treated Time
Description
References
PC-9/PEM clone1
1 μM
96 h
Defactinib combined with EGFR-TKI significantly induced apoptosis
Respir Res. 2019 Dec 2;20(1):270.
PDAC-1
1μM
24 h
Defactinib significantly inhibited the migration ability of PDAC cells.
J Exp Clin Cancer Res. 2021 Mar 9;40(1):91.
MDA-MB-231
10 µM
18 h
Defactinib inhibited NGF-induced migration of MDA-MB-231 cells.
Front Cell Dev Biol. 2021 Jun 29;9:676568.
MDA-MB-453
10 µM
18 h
Defactinib inhibited NGF-induced migration of MDA-MB-453 cells.
Front Cell Dev Biol. 2021 Jun 29;9:676568.
PC-9/PEM
3 μM
96 h
Defactinib inhibited PTK2 phosphorylation and restored EGFR-TKI sensitivity
Respir Res. 2019 Dec 2;20(1):270.
Cdh1−/−RHOAY42C/+ organoids
2.5 μM
20 days
To evaluate the inhibitory effect of Defactinib on Cdh1−/−RHOAY42C/+ organoids, it was found that CDK6 promoted resistance to Defactinib.
Clin Cancer Res. 2023 Jan 4;29(1):197-208.
SNU668 cells
2.5 μM
To validate whether CDK6 overexpression promotes resistance to Defactinib, results showed that CDK6 indeed promoted resistance to Defactinib.
Clin Cancer Res. 2023 Jan 4;29(1):197-208.
Suit-2
2.0–5.0μM
72 h
Defactinib reduced PDAC cell proliferation, validating the anti-tumor effect of FAK inhibition.
J Exp Clin Cancer Res. 2021 Mar 9;40(1):91.
MCF10A cells
5 μM
24 h
Assessed the effect of Defactinib on MCF10A cells, no cytotoxicity observed.
Nat Mater. 2020 Jul;19(7):797-806.
FM-93/2
5 µM
96 h
Evaluate the effect of Defactinib on FM-93/2 cells, results showed AMBRA1LOW cells are more sensitive to FAKi
Proc Natl Acad Sci U S A. 2024 Jun 18;121(25):e2400566121.
M24
5 µM
96 h
Evaluate the effect of Defactinib on M24 cells, results showed AMBRA1LOW cells are more sensitive to FAKi
Proc Natl Acad Sci U S A. 2024 Jun 18;121(25):e2400566121.
Defactinib/地法替尼 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
BALB/cA nu/nu mice
Subcutaneous xenograft model
Oral
25 mg/kg/d
Twice daily for 5 days/week
Combination of defactinib and osimertinib significantly inhibited tumor growth
Respir Res. 2019 Dec 2;20(1):270.
NSG mice
NUGC4 and SNU668 xenograft models
Oral
50 mg/kg
Twice daily for 3 weeks
To evaluate the effect of Defactinib combined with CDK4/6 inhibitors, results showed that the combination therapy significantly inhibited tumor growth.
Clin Cancer Res. 2023 Jan 4;29(1):197-208.
Mice
FC1199 pancreatic cancer model
Oral
15 mg/kg
Twice daily for 12 days
To test the inhibitory effect of Defactinib combined with Erdafitinib on the FC1199 pancreatic cancer model, the results showed that the combination significantly inhibited tumor growth.
J Exp Clin Cancer Res. 2023 Aug 9;42(1):201
Nude mice
Orthotopic xenograft HCC model
Oral
25 mg/kg
Twice daily for eight weeks
The combination of Defactinib and Linsitinib significantly suppressed BACH1-mediated HCC tumor growth and lung metastasis, and prolonged the survival of nude mice
Theranostics. 2022 Jan 1;12(3):1097-1116
Nude mice
Orthotopic pancreatic cancer model
Oral
25 mg/kg
Twice daily for 2 cycles, each cycle lasting 5 days
The combination of defactinib with nab-paclitaxel significantly inhibited tumor growth, while defactinib alone showed limited efficacy.
J Exp Clin Cancer Res. 2021 Mar 9;40(1):91.
C57 BL/6 mice
MC38 subcutaneous tumor model
Intraperitoneal injection
10 mg/kg
Daily for one week
Inhibition of PYK2 or integrin β1 by Defactinib reduced SPON2-induced tumor growth and M2-TAMs infiltration.
J Exp Clin Cancer Res. 2021 Sep 28;40(1):304
Mice
C57Bl/6 N mice
Oral
50 mg/kg
21 days
Evaluate the effect of Defactinib on mouse models, results showed FAKi alone or in combination with BRAFi can overcome BRAFi resistance
Proc Natl Acad Sci U S A. 2024 Jun 18;121(25):e2400566121.
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