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Inhibition of mTOR pathway by everolimus cooperates with EGFR inhibitors in human tumours sensitive and resistant to anti-EGFR drugs.

Bianco R, Garofalo S, Rosa R, Damiano V, Gelardi T, Daniele G, Marciano R, Ciardiello F, Tortora G - Br. J. Cancer (2008)

Bottom Line: Everolimus reduces the expression of EGFR-related signalling effectors and VEGF production, inhibiting proliferation and capillary tube formation of endothelial cells, both alone and in combination with gefitinib.Finally, combination of everolimus and gefitinib inhibits growth of GEO and GEO-GR (gefitinib resistant) colon cancer xenografts, activation of signalling proteins and VEGF secretion.Targeting mTOR pathway with everolimus overcomes resistance to EGFR inhibitors and produces a cooperative effect with EGFR inhibitors, providing a valid therapeutic strategy to be tested in a clinical setting.

View Article: PubMed Central - PubMed

Affiliation: Cattedra di Oncologia Medica, Dipartimento Endocrinologia e Oncologia Molecolare e Clinica, Università di Napoli Federico II, via S. Pansini 5, Napoli 80131, Italy.

ABSTRACT
Inhibition of a single transduction pathway is often inefficient due to activation of alternative signalling. The mammalian target of rapamycin (mTOR) is a key intracellular kinase integrating proliferation, survival and angiogenic pathways and has been implicated in the resistance to EGFR inhibitors. Thus, mTOR blockade is pursued to interfere at multiple levels with tumour growth. We used everolimus (RAD001) to inhibit mTOR, alone or in combination with anti-EGFR drugs gefitinib or cetuximab, on human cancer cell lines sensitive and resistant to EGFR inhibitors, both in vitro and in vivo. We demonstrated that everolimus is active against EGFR-resistant cancer cell lines and partially restores the ability of EGFR inhibitors to inhibit growth and survival. Everolimus reduces the expression of EGFR-related signalling effectors and VEGF production, inhibiting proliferation and capillary tube formation of endothelial cells, both alone and in combination with gefitinib. Finally, combination of everolimus and gefitinib inhibits growth of GEO and GEO-GR (gefitinib resistant) colon cancer xenografts, activation of signalling proteins and VEGF secretion. Targeting mTOR pathway with everolimus overcomes resistance to EGFR inhibitors and produces a cooperative effect with EGFR inhibitors, providing a valid therapeutic strategy to be tested in a clinical setting.

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Related in: MedlinePlus

(A and B) After 7 days following tumour injection, 10 mice were treated. Tumour sizes among different treatment groups at day 56 following GEO or GEO-GR cell injection resulted statistically significant for everolimus plus gefitinib vs control, vs everolimus alone and vs gefitinib alone (two-sided P<0.0001). Bars, s.d. (C and D) Mice survival resulted statistically significant for everolimus plus gefitinib vs control, vs everolimus alone and vs gefitinib alone (two-sided P<0.0001).
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fig4: (A and B) After 7 days following tumour injection, 10 mice were treated. Tumour sizes among different treatment groups at day 56 following GEO or GEO-GR cell injection resulted statistically significant for everolimus plus gefitinib vs control, vs everolimus alone and vs gefitinib alone (two-sided P<0.0001). Bars, s.d. (C and D) Mice survival resulted statistically significant for everolimus plus gefitinib vs control, vs everolimus alone and vs gefitinib alone (two-sided P<0.0001).

Mentions: To further investigate the role of everolimus on cancer cells resistant to EGFR inhibitors, we established GEO and GEO-GR xenografts by using BalbC nude mice. As expected, treatment with gefitinib alone was effective on GEO xenografts, but ineffective on GEO-GR xenografts, because, on day 56, all mice in this group reached the maximum allowed tumour size of about 2 cm3. Conversely, treatment with everolimus produced a 50% tumour growth inhibition, with an average tumour size of about 1.0 cm3 at the same time point in both xenograft models. The combination of everolimus and gefitinib caused a cooperative antitumour activity, resulting in over 90% tumour growth inhibition on day 56 (tumour size of about 0.2 cm3) not only in GEO, but also in GEO-GR-xenografted mice (Figure 4A and B). At the end of the experiment, 10 weeks after treatment withdrawal, GEO-GR tumour growth inhibition was still evident and tumour size was about 1 cm3 (Figure 4B). Comparison of tumour sizes among different treatment groups, evaluated by the Student's t-test, was statistically significant.


Inhibition of mTOR pathway by everolimus cooperates with EGFR inhibitors in human tumours sensitive and resistant to anti-EGFR drugs.

Bianco R, Garofalo S, Rosa R, Damiano V, Gelardi T, Daniele G, Marciano R, Ciardiello F, Tortora G - Br. J. Cancer (2008)

(A and B) After 7 days following tumour injection, 10 mice were treated. Tumour sizes among different treatment groups at day 56 following GEO or GEO-GR cell injection resulted statistically significant for everolimus plus gefitinib vs control, vs everolimus alone and vs gefitinib alone (two-sided P<0.0001). Bars, s.d. (C and D) Mice survival resulted statistically significant for everolimus plus gefitinib vs control, vs everolimus alone and vs gefitinib alone (two-sided P<0.0001).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2266842&req=5

fig4: (A and B) After 7 days following tumour injection, 10 mice were treated. Tumour sizes among different treatment groups at day 56 following GEO or GEO-GR cell injection resulted statistically significant for everolimus plus gefitinib vs control, vs everolimus alone and vs gefitinib alone (two-sided P<0.0001). Bars, s.d. (C and D) Mice survival resulted statistically significant for everolimus plus gefitinib vs control, vs everolimus alone and vs gefitinib alone (two-sided P<0.0001).
Mentions: To further investigate the role of everolimus on cancer cells resistant to EGFR inhibitors, we established GEO and GEO-GR xenografts by using BalbC nude mice. As expected, treatment with gefitinib alone was effective on GEO xenografts, but ineffective on GEO-GR xenografts, because, on day 56, all mice in this group reached the maximum allowed tumour size of about 2 cm3. Conversely, treatment with everolimus produced a 50% tumour growth inhibition, with an average tumour size of about 1.0 cm3 at the same time point in both xenograft models. The combination of everolimus and gefitinib caused a cooperative antitumour activity, resulting in over 90% tumour growth inhibition on day 56 (tumour size of about 0.2 cm3) not only in GEO, but also in GEO-GR-xenografted mice (Figure 4A and B). At the end of the experiment, 10 weeks after treatment withdrawal, GEO-GR tumour growth inhibition was still evident and tumour size was about 1 cm3 (Figure 4B). Comparison of tumour sizes among different treatment groups, evaluated by the Student's t-test, was statistically significant.

Bottom Line: Everolimus reduces the expression of EGFR-related signalling effectors and VEGF production, inhibiting proliferation and capillary tube formation of endothelial cells, both alone and in combination with gefitinib.Finally, combination of everolimus and gefitinib inhibits growth of GEO and GEO-GR (gefitinib resistant) colon cancer xenografts, activation of signalling proteins and VEGF secretion.Targeting mTOR pathway with everolimus overcomes resistance to EGFR inhibitors and produces a cooperative effect with EGFR inhibitors, providing a valid therapeutic strategy to be tested in a clinical setting.

View Article: PubMed Central - PubMed

Affiliation: Cattedra di Oncologia Medica, Dipartimento Endocrinologia e Oncologia Molecolare e Clinica, Università di Napoli Federico II, via S. Pansini 5, Napoli 80131, Italy.

ABSTRACT
Inhibition of a single transduction pathway is often inefficient due to activation of alternative signalling. The mammalian target of rapamycin (mTOR) is a key intracellular kinase integrating proliferation, survival and angiogenic pathways and has been implicated in the resistance to EGFR inhibitors. Thus, mTOR blockade is pursued to interfere at multiple levels with tumour growth. We used everolimus (RAD001) to inhibit mTOR, alone or in combination with anti-EGFR drugs gefitinib or cetuximab, on human cancer cell lines sensitive and resistant to EGFR inhibitors, both in vitro and in vivo. We demonstrated that everolimus is active against EGFR-resistant cancer cell lines and partially restores the ability of EGFR inhibitors to inhibit growth and survival. Everolimus reduces the expression of EGFR-related signalling effectors and VEGF production, inhibiting proliferation and capillary tube formation of endothelial cells, both alone and in combination with gefitinib. Finally, combination of everolimus and gefitinib inhibits growth of GEO and GEO-GR (gefitinib resistant) colon cancer xenografts, activation of signalling proteins and VEGF secretion. Targeting mTOR pathway with everolimus overcomes resistance to EGFR inhibitors and produces a cooperative effect with EGFR inhibitors, providing a valid therapeutic strategy to be tested in a clinical setting.

Show MeSH
Related in: MedlinePlus