Identification of c-Src as a Potential Therapeutic Target for Gastric Cancer and of MET Activation as a Cause of Resistance to c-Src Inhibition

Okamoto, Wataru; Okamoto, Isamu; Yoshida, Takeshi; Okamoto, Kunio; Takezawa, Ken; Hatashita, Erina; Yamada, Yoshiaki; Kuwata, Kiyoko; Arao, Tokuzo; Yanagihara, Kazuyoshi; Fukuoka, Masahiro; Nishio, Kazuto; Nakagawa, Kazuhiko

doi:10.1158/1535-7163.mct-10-0002

Cited by 62 publications

(68 citation statements)

References 33 publications

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“…Western blotting analysis was performed in four gastric cell lines as described previously [27]. Cells were incubated in the absence or presence of 0.05 nM crizotinib for 48 h, after which cell lysates were prepared and subjected to western blotting analysis.…”

Section: Western Blottingmentioning

confidence: 99%

MET overexpression and amplification define a distinct molecular subgroup for targeted therapies in gastric cancer

Yang

Shen

et al. 2015

Gastric Cancer

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Background Currently, only trastuzumab, ramucirumab, and apatinib effectively treat gastric cancer. Thus, additional novel targets are required for this disease. Methods We investigated the immunohistochemical and fluorescence in situ hybridization expression of MET, ROS1, and ALK in four gastric cell lines and a cohort of 98 gastric cancer patients. Crizotinib response was studied in vitro and in vivo. Results Crizotinib potently inhibited in vitro cell growth in only one cell line, which also showed MET amplification. A positive correlation between crizotinib sensitivity and MET overexpression was observed (P = 0.045) in the histoculture drug response assay. Meanwhile, patientderived tumor xenograft mouse models transplanted with tissues with higher MET protein expression displayed a highly selective sensitivity to crizotinib. In the 98 patients, MET overexpression was found in 42 (42.9 %) and MET was amplified in 4 (4.1 %). ROS1 and ALK overexpression were found in 25 (25.5 %) and 0 patients, respectively. However, none of the patients screened harbored ALK or ROS1 rearrangements. No significant association was found between overall survival and MET or ROS1 status. We also observed a stage IV gastric cancer patient with MET amplification who experienced tumor shrinkage and clinical benefit after 3 weeks of crizotinib as fourth-line treatment. Conclusions Crizotinib may induce clinically relevant anticancer effects in MET-overexpressed or MET-amplified gastric cancer patients.

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Section: Western Blottingmentioning

confidence: 99%

MET overexpression and amplification define a distinct molecular subgroup for targeted therapies in gastric cancer

Yang

Shen

et al. 2015

Gastric Cancer

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“…Human gastric cancer cell lines positive (SNU5, Hs746T, MKN45, HSC58, 58As1, 58As9) or negative (SNU1, N87, AGS, MKN1, MKN7, NUGC3, AZ521, MKN28, HSC39, SNU216) for MET amplification were obtained as previously described (8,11). All cells were cultured under a humidified atmosphere of 5% CO 2 at 37 C in RPMI-1640 medium (Sigma) supplemented with 10% FBS and were passaged for 3 months before renewal from frozen early-passage stocks obtained from the respective sources.…”

Section: Cell Culture and Reagentsmentioning

confidence: 99%

“…Substantial advances in the development of molecularly targeted therapies for gastric cancer have been achieved in recent years (3). Amplification of the proto-oncogene MET is a frequent molecular abnormality in gastric cancer (4)(5)(6), and a MET-tyrosine kinase inhibitor (TKI) has been shown to induce apoptosis in gastric cancer cells with MET amplification (7,8).…”

Section: Introductionmentioning

confidence: 99%

Antitumor Action of the MET Tyrosine Kinase Inhibitor Crizotinib (PF-02341066) in Gastric Cancer Positive for MET Amplification

Okamoto

Arao

et al. 2012

Molecular Cancer Therapeutics

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Therapeutic strategies that target the tyrosine kinase MET hold promise for gastric cancer, but the mechanism underlying the antitumor activity of such strategies remains unclear. We examined the antitumor action of the MET tyrosine kinase inhibitor crizotinib (PF-02341066) in gastric cancer cells positive or negative for MET amplification. Inhibition of MET signaling by crizotinib or RNA interference-mediated MET depletion resulted in induction of apoptosis accompanied by inhibition of AKT and extracellular signal-regulated kinase phosphorylation in gastric cancer cells with MET amplification but not in those without it, suggesting that MET signaling is essential for the survival of MET amplification-positive cells. Crizotinib upregulated the expression of BIM, a proapoptotic member of the Bcl-2 family, as well as downregulated that of survivin, X-linked inhibitor of apoptosis protein (XIAP), and c-IAP1, members of the inhibitor of apoptosis protein family, in cells with MET amplification. Forced depletion of BIM inhibited crizotinib-induced apoptosis, suggesting that upregulation of BIM contributes to the proapoptotic effect of crizotinib. Crizotinib also exhibited a marked antitumor effect in gastric cancer xenografts positive for MET amplification, whereas it had little effect on those negative for this genetic change. Crizotinib thus shows a marked antitumor action both in vitro and in vivo specifically in gastric cancer cells positive for MET amplification.

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“…Src activity is also increased in gastric cancer (7,8). The presence of activated Src in gastric cancer along with the role of this factor in cancer cell proliferation and metastasis raise the possibility that Src is a promising target for treating gastric cancer.…”

Section: Introductionmentioning

confidence: 99%

Antitumor Activity of Saracatinib (AZD0530), a c-Src/Abl Kinase Inhibitor, Alone or in Combination with Chemotherapeutic Agents in Gastric Cancer

Nam

et al. 2013

Molecular Cancer Therapeutics

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Src is a nonreceptor tyrosine kinase involved in the cross-talk and mediation of many signaling pathways that promote cell proliferation, adhesion, invasion, migration, and tumorigenesis. Increased Src activity has been reported in many types of human cancer, including gastric cancer. Therefore, this factor has been identified as a promising therapeutic target for cancer treatments, and targeting Src in gastric cancer is predicted to have potent effects. We evaluated the antitumor effect of a c-Src/Abl kinase inhibitor, saracatinib (AZD0530), alone or combined with chemotherapeutic agents in gastric cancer cell lines and a NCI-N87 xenograft model. Among 10 gastric cancer cell lines, saracatinib specifically inhibited the growth and migration/invasion of SNU216 and NCI-N87 cells. Saracatinib blocked the Src/FAK, HER family, and oncogenic signaling pathways, and it induced G 1 arrest and apoptosis in SNU216 and NCI-N87 cells. Apoptosis required induction of the proapoptotic BCL2 family member Bim. Knockdown of Bim using siRNA decreased apoptosis induced by treatment with saracatinib, suggesting that Bim has an important role in saracatinibinduced apoptosis. Saracatinib enhanced the effects of lapatinib, an EGFR/HER2 dual inhibitor, in SNU216 and NCI-N87 cells. Furthermore, combined treatment with saracatinib and 5-fluorouracil (5-FU) or cisplatin exerted synergistic effects in both saracatinib-sensitive and saracatinib-resistant cells. Consistent with our in vitro findings, cotreatment with saracatinib and 5-FU resulted in enhanced antitumor activity in the NCI-N87 xenografts. These data indicate that the inhibition of Src kinase activity by saracatinib alone or in combination with other agents can be a strategy to target gastric cancer.

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Identification of c-Src as a Potential Therapeutic Target for Gastric Cancer and of MET Activation as a Cause of Resistance to c-Src Inhibition

Cited by 62 publications

References 33 publications

MET overexpression and amplification define a distinct molecular subgroup for targeted therapies in gastric cancer

MET overexpression and amplification define a distinct molecular subgroup for targeted therapies in gastric cancer

Antitumor Action of the MET Tyrosine Kinase Inhibitor Crizotinib (PF-02341066) in Gastric Cancer Positive for MET Amplification

Antitumor Activity of Saracatinib (AZD0530), a c-Src/Abl Kinase Inhibitor, Alone or in Combination with Chemotherapeutic Agents in Gastric Cancer

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