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Multiple receptor tyrosine kinase activation attenuates therapeutic efficacy of the fibroblast growth factor receptor 2 inhibitor AZD4547 in FGFR2 amplified gastric cancer.

Chang J, Wang S, Zhang Z, Liu X, Wu Z, Geng R, Ge X, Dai C, Liu R, Zhang Q, Li W, Li J - Oncotarget (2015)

Bottom Line: However, intrinsic or acquired drug resistance has emerged as a major challenge to their clinical use.The rescue effect was abrogated by inhibiting these RTKs with their targeted tyrosine kinase inhibitors (TKIs).A combination targeted therapeutic strategy may be recommended for treating FGFR2 amplified GC patients with these RTK activations.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.

ABSTRACT
Fibroblast growth factor receptor 2 (FGFR2)-targeted therapy has attracted considerable attention as novel anticancer agents in gastric cancer (GC). However, intrinsic or acquired drug resistance has emerged as a major challenge to their clinical use. In this study, we demonstrated that several receptor tyrosine kinase (RTK), including EGFR, HER3 and MET, activations contributed to AZD4547 (a selective FGFR2 inhibitor) hyposensitivity in FGFR2 amplified GC cells. The rescue effect was abrogated by inhibiting these RTKs with their targeted tyrosine kinase inhibitors (TKIs). In addition, synergy in growth inhibition was observed when the GC cells were treated with a combination of AZD4547 and cetuximab (an EGFR monoclonal antibody) both in vitro and in vivo. More importantly, tissue microarray analysis revealed that these resistance-conferring RTKs were highly expressed in FGFR2 positive GC patients. Taken together, these observations demonstrated RTKs including EGFR, HER3 and MET activations as novel mechanisms of hyposensitivity to AZD4547. It will be clinically valuable to investigate the involvement of RTK-mediated signaling in intrinsicor acquired resistance to FGFR2 TKIs in GC. A combination targeted therapeutic strategy may be recommended for treating FGFR2 amplified GC patients with these RTK activations.

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FGFR2 gene amplification predicts AZD4547 sensitivity in GC cellsA) Detection of FGFR2 gene amplification in CG cells by qPCR analysis. B) Western blot analyses confirming high expression of FGFR2 proteins from cell lines with FGFR2 gene amplification. C) FGFR2-amplified GC cells are selectively sensitive to AZD4547. In vitro CCK-8 assay across a panel of 6 GC cells demonstrated that SNU16 and KATOIII cells were extremely sensitive to AZD4547 with IC50 values of 5-10 nM. Data (n = 6) are presented as mean ± SD. D) AZD4547 inhibits FGFR2 pathway activation in SNU16 and KATOIII cells. Cells were incubated with AZD4547 at the indicated doses. Cell lysates were immunoblotted for phospho-FGFR, phospho-FRS2, phospho- and total AKT, and phospho- and total ERK.
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Figure 1: FGFR2 gene amplification predicts AZD4547 sensitivity in GC cellsA) Detection of FGFR2 gene amplification in CG cells by qPCR analysis. B) Western blot analyses confirming high expression of FGFR2 proteins from cell lines with FGFR2 gene amplification. C) FGFR2-amplified GC cells are selectively sensitive to AZD4547. In vitro CCK-8 assay across a panel of 6 GC cells demonstrated that SNU16 and KATOIII cells were extremely sensitive to AZD4547 with IC50 values of 5-10 nM. Data (n = 6) are presented as mean ± SD. D) AZD4547 inhibits FGFR2 pathway activation in SNU16 and KATOIII cells. Cells were incubated with AZD4547 at the indicated doses. Cell lysates were immunoblotted for phospho-FGFR, phospho-FRS2, phospho- and total AKT, and phospho- and total ERK.

Mentions: To select FGFR2 amplified GC cells, we first tested a panel of GC cell lines (SNU16, KATOIII, HGC-27, MKN-28, MKN-45, SGC7901 and NCI-N87) for their degrees of FGFR2 gene amplification and protein expression. As shown in Fig. 1A, quantitative polymerase chain reaction (PCR) determined that SNU16 and KATOIII cells were FGFR2 gene amplified, and the rest of the cell lines were not FGFR2 gene amplified. The degree of FGFR2 amplification in SNU16 and KATOIII cells corresponded to overexpression of FGFR2 proteins in these cells (Fig. 1B).


Multiple receptor tyrosine kinase activation attenuates therapeutic efficacy of the fibroblast growth factor receptor 2 inhibitor AZD4547 in FGFR2 amplified gastric cancer.

Chang J, Wang S, Zhang Z, Liu X, Wu Z, Geng R, Ge X, Dai C, Liu R, Zhang Q, Li W, Li J - Oncotarget (2015)

FGFR2 gene amplification predicts AZD4547 sensitivity in GC cellsA) Detection of FGFR2 gene amplification in CG cells by qPCR analysis. B) Western blot analyses confirming high expression of FGFR2 proteins from cell lines with FGFR2 gene amplification. C) FGFR2-amplified GC cells are selectively sensitive to AZD4547. In vitro CCK-8 assay across a panel of 6 GC cells demonstrated that SNU16 and KATOIII cells were extremely sensitive to AZD4547 with IC50 values of 5-10 nM. Data (n = 6) are presented as mean ± SD. D) AZD4547 inhibits FGFR2 pathway activation in SNU16 and KATOIII cells. Cells were incubated with AZD4547 at the indicated doses. Cell lysates were immunoblotted for phospho-FGFR, phospho-FRS2, phospho- and total AKT, and phospho- and total ERK.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4385832&req=5

Figure 1: FGFR2 gene amplification predicts AZD4547 sensitivity in GC cellsA) Detection of FGFR2 gene amplification in CG cells by qPCR analysis. B) Western blot analyses confirming high expression of FGFR2 proteins from cell lines with FGFR2 gene amplification. C) FGFR2-amplified GC cells are selectively sensitive to AZD4547. In vitro CCK-8 assay across a panel of 6 GC cells demonstrated that SNU16 and KATOIII cells were extremely sensitive to AZD4547 with IC50 values of 5-10 nM. Data (n = 6) are presented as mean ± SD. D) AZD4547 inhibits FGFR2 pathway activation in SNU16 and KATOIII cells. Cells were incubated with AZD4547 at the indicated doses. Cell lysates were immunoblotted for phospho-FGFR, phospho-FRS2, phospho- and total AKT, and phospho- and total ERK.
Mentions: To select FGFR2 amplified GC cells, we first tested a panel of GC cell lines (SNU16, KATOIII, HGC-27, MKN-28, MKN-45, SGC7901 and NCI-N87) for their degrees of FGFR2 gene amplification and protein expression. As shown in Fig. 1A, quantitative polymerase chain reaction (PCR) determined that SNU16 and KATOIII cells were FGFR2 gene amplified, and the rest of the cell lines were not FGFR2 gene amplified. The degree of FGFR2 amplification in SNU16 and KATOIII cells corresponded to overexpression of FGFR2 proteins in these cells (Fig. 1B).

Bottom Line: However, intrinsic or acquired drug resistance has emerged as a major challenge to their clinical use.The rescue effect was abrogated by inhibiting these RTKs with their targeted tyrosine kinase inhibitors (TKIs).A combination targeted therapeutic strategy may be recommended for treating FGFR2 amplified GC patients with these RTK activations.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.

ABSTRACT
Fibroblast growth factor receptor 2 (FGFR2)-targeted therapy has attracted considerable attention as novel anticancer agents in gastric cancer (GC). However, intrinsic or acquired drug resistance has emerged as a major challenge to their clinical use. In this study, we demonstrated that several receptor tyrosine kinase (RTK), including EGFR, HER3 and MET, activations contributed to AZD4547 (a selective FGFR2 inhibitor) hyposensitivity in FGFR2 amplified GC cells. The rescue effect was abrogated by inhibiting these RTKs with their targeted tyrosine kinase inhibitors (TKIs). In addition, synergy in growth inhibition was observed when the GC cells were treated with a combination of AZD4547 and cetuximab (an EGFR monoclonal antibody) both in vitro and in vivo. More importantly, tissue microarray analysis revealed that these resistance-conferring RTKs were highly expressed in FGFR2 positive GC patients. Taken together, these observations demonstrated RTKs including EGFR, HER3 and MET activations as novel mechanisms of hyposensitivity to AZD4547. It will be clinically valuable to investigate the involvement of RTK-mediated signaling in intrinsicor acquired resistance to FGFR2 TKIs in GC. A combination targeted therapeutic strategy may be recommended for treating FGFR2 amplified GC patients with these RTK activations.

Show MeSH
Related in: MedlinePlus