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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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Representative example of FISH analysis of FGFR2 gene status from a cohort of GC specimens (n = 145)Left panel is a non-amplified sample, right is an amplified sample. Red signals represent CEP10 genes whist green signals are FGFR2 (original magnification × 1000).
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Figure 6: Representative example of FISH analysis of FGFR2 gene status from a cohort of GC specimens (n = 145)Left panel is a non-amplified sample, right is an amplified sample. Red signals represent CEP10 genes whist green signals are FGFR2 (original magnification × 1000).

Mentions: Moreover, we performed FISH analysis to evaluate FGFR2 gene amplification status and its association with FGFR2 as well as other RTKs expression level (see Fig. 6). As a result, 4 samples from a total of 145 samples were identified as FGFR2 amplified. In these four cases, two cases were FGFR2 2+ while the other two were FGFR2 3+ by IHC assay. Furthermore, the positivity of HER3, EGFR and MET in these four samples were detected in 3 (75%), 3 (75%) and 1 (25%) samples. Taken together, the data from tissue microarray analysis (TMA) in our study revealed that intrinsic resistance-conferring RTKs were commonly enriched in FGFR2 positive GC, indicating the potential clinical application of our preclinical studies.


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)

Representative example of FISH analysis of FGFR2 gene status from a cohort of GC specimens (n = 145)Left panel is a non-amplified sample, right is an amplified sample. Red signals represent CEP10 genes whist green signals are FGFR2 (original magnification × 1000).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: Representative example of FISH analysis of FGFR2 gene status from a cohort of GC specimens (n = 145)Left panel is a non-amplified sample, right is an amplified sample. Red signals represent CEP10 genes whist green signals are FGFR2 (original magnification × 1000).
Mentions: Moreover, we performed FISH analysis to evaluate FGFR2 gene amplification status and its association with FGFR2 as well as other RTKs expression level (see Fig. 6). As a result, 4 samples from a total of 145 samples were identified as FGFR2 amplified. In these four cases, two cases were FGFR2 2+ while the other two were FGFR2 3+ by IHC assay. Furthermore, the positivity of HER3, EGFR and MET in these four samples were detected in 3 (75%), 3 (75%) and 1 (25%) samples. Taken together, the data from tissue microarray analysis (TMA) in our study revealed that intrinsic resistance-conferring RTKs were commonly enriched in FGFR2 positive GC, indicating the potential clinical application of our preclinical studies.

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