Combination therapy with zoledronic acid and cetuximab effectively suppresses growth of colorectal cancer cells regardless of <scp><i>KRAS</i></scp> status

Kato, Jun; Futamura, Manabu; Kanematsu, M; Gaowa, Siqin; Mori, Rintaro; Tanahashi, Takao; Matsuhashi, Nobuhisa; Yoshida, Kazuhiro

doi:10.1002/ijc.29881

Cited by 16 publications

(13 citation statements)

References 42 publications

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“…We previously reported that the addition of zoledronic acid to anti-EGFR therapy results in tumor-growth suppression, even in KRAS -mutated CRC cells 41 . This strategy can correct both the AKT- and MAPK-signaling pathways and enhance the effect of anti-EGFR therapy, and it is possible that this additional treatment might help to enhance the effects of anti-GPNMB and anti-EGFR/HER2 therapy.…”

Section: Discussionmentioning

confidence: 99%

Clinical Significance of Glycoprotein Non-metastatic B and Its Association with EGFR/HER2 in Gastrointestinal Cancer

et al. 2018

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Glycoprotein non-metastatic B (GPNMB), a type I transmembrane glycoprotein, is overexpressed in melanoma and breast cancer and promotes cancer-cell invasion and motility. We previously reported cross-talk between GPNMB and human epidermal growth factor receptor 2 (HER2) in breast cancer, suggesting that GPNMB might play an important role in resistance to anti-HER2 therapy in breast cancer. Here, we clarified the association between GPNMB and HER-family proteins in gastrointestinal cancer by examining their relationships using gastric and colorectal cancer cell lines. We found that GPNMB depletion of by small-interfering RNA increased epidermal growth factor receptor (EGFR) expression and phosphorylation through AKT8 virus oncogene cellular homolog (AKT) and mitogen-activated protein kinase (MAPK) pathways. Additionally, treatment with cetuximab (CTX) also increased GPNMB expression, and combination therapy consisting of GPNMB depletion and CTX treatment significantly suppressed cell growth in colorectal cancer cell lines, but not in gastric cancer cell lines. Furthermore, we also evaluated changes in GPNMB expression in vivo, with immunohistochemistry detecting GPNMB overexpression in a colorectal cancer patient following anti-EGFR therapy. These results suggested possible cross-talk between GPNMB and EGFR, and that GPNMB might play an important role in resistance to anti-EGFR therapy in gastrointestinal cancer.

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Section: Discussionmentioning

confidence: 99%

Clinical Significance of Glycoprotein Non-metastatic B and Its Association with EGFR/HER2 in Gastrointestinal Cancer

et al. 2018

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“…Our experiments showed that Ixazomib elicited a significant growth-inhibitory effect in both colorectal cell lines, as evidenced by a reduction in cell viability in vitro and the reduction of tumor growth rates in vivo . SW1222 tumors were found to be more sensitive to Ixazomib than LS174T tumors, which could be due to their different K-Ras mutations: SW1222 cells have a K-Ras mutation at A146V 35 , compared with G12D for LS174T tumors 36 , which has been proposed to infer a greater sensitivity to proteasome inhibition 9 . In addition, the microenvironment of the two tumor types could provide a source of resistance in vivo , with LS174T tumors being less vascular, less differentiated and less perfused than SW1222 tumors 37 – 39 .…”

Section: Discussionmentioning

confidence: 99%

Non-invasive imaging of disrupted protein homeostasis induced by proteasome inhibitor treatment using chemical exchange saturation transfer MRI

Zhu

Ramasawmy

Johnson

et al. 2018

Sci Rep

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Proteasome inhibitors (PIs) are now standard of care for several cancers, and noninvasive biomarkers of treatment response are critically required for early patient stratification and treatment personalization. The present study evaluated whether chemical exchange (CEST) magnetic resonance imaging (MRI) can provide measurements that can be used as the noninvasive biomarkers of proteasome inhibition, alongside diffusion MRI and relaxometry. The sensitivity of human colorectal carcinoma cells to the PI Ixazomib was assessed via in vitro and in vivo dose-response experiments. Acute in vivo response to Ixazomib was assessed at three dosing concentrations, using CEST MRI (amide, amine, hydroxyl signals), diffusion MRI (ADC) and relaxometry (T1, T2). These responses were further evaluated with the known histological markers for Ixazomib and Bradford assay ex vivo. The CEST signal from amides and amines increased in proportion to Ixazomib dose in colorectal cancer xenografts. The cell lines differed in their sensitivity to Ixazomib, which was reflected in the MRI measurements. A mild stimulation in tumor growth was observed at low Ixazomib doses. Our results identify CEST MRI as a promising method for safely and noninvasively monitoring disrupted tumor protein homeostasis induced by proteasome inhibitor treatment, and for stratifying sensitivity between tumor types.

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“…Our experiments showed that ixazomib elicited a significant growth-inhibitory effect in both colorectal cell lines, as evidenced by a reduction in cell viability in vitro and in the reduction of tumor growth rates in vivo. SW1222 tumors were found to be more sensitive to ixazomib than LS174T tumors, which could be due to their different K-Ras mutations: SW1222 cells have a K-Ras mutation at A146V (35), compared with G12D for LS174T tumors (36), which has been proposed to infer a greater sensitivity to proteosome inhibition (11). In addition, the microenvironment of the two tumor types could provide a source of resistance in vivo, with LS174T tumors being less vascular, less differentiated and less perfused than SW1222 tumors (37-39).…”

Section: Discussionmentioning

confidence: 99%

Development of noninvasive biomarkers of response to proteasome inhibitor therapy (ixazomib) by imaging disrupted protein homeostasis in mouse models of solid tumors

Zhu

Ramasawmy

et al. 2017

Preprint

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With clinically-approved proteasome inhibitors now a standard of care for multiple myeloma, and increasing interest in their use in solid tumors, methods for monitoring therapeutic response in vivo are critically required. Here, we show that tumor protein homeostasis can be noninvasively monitored, using chemical exchange (CEST) magnetic resonance imaging (MRI) as a surrogate marker for proteasome inhibition, alongside diffusion MRI and relaxometry. We show that the in vivo CEST signal associated with amides and amines increases in proportion to proteasome inhibitor dose (ixazomib) and the magnitude of therapeutic effect in colorectal cancer xenografts. Moreover, we show that SW1222 and LS174T human colorectal cancer cell lines demonstrate differing sensitivities to ixazomib, which was reflected in our MRI measurements. We also found evidence of a mild stimulation in tumor growth at low ixazomib doses. Our results therefore identify CEST MRI as a promising method for safely and noninvasively monitoring changes in tumor protein homeostasis.

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Combination therapy with zoledronic acid and cetuximab effectively suppresses growth of colorectal cancer cells regardless of KRAS status

Cited by 16 publications

References 42 publications

Clinical Significance of Glycoprotein Non-metastatic B and Its Association with EGFR/HER2 in Gastrointestinal Cancer

Clinical Significance of Glycoprotein Non-metastatic B and Its Association with EGFR/HER2 in Gastrointestinal Cancer

Non-invasive imaging of disrupted protein homeostasis induced by proteasome inhibitor treatment using chemical exchange saturation transfer MRI

Development of noninvasive biomarkers of response to proteasome inhibitor therapy (ixazomib) by imaging disrupted protein homeostasis in mouse models of solid tumors

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