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[Mechanism Underlying Pancreatic Cancer Cell Resistance to mTOR Inhibitor RAD001 via c-Raf/ERK1/2 Activation]

[Mechanism Underlying Pancreatic Cancer Cell Resistance to mTOR Inhibitor RAD001 via c-Raf/ERK1/2 Activation]

Feng Wei, Ping Zhang, Jun Qi, Meng Wang, Guangyi Wang

Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2014 Jan;30(1):23-7.

PMID: 24405594

Abstract:

Objective:
To investigate the molecular mechanism of pancreatic cancer cell resistance to mammalian target of rapamycin (mTOR) inhibitor RAD001, and explore a feasible therapeutic strategy to overcome the resistance in patients with pancreatic cancer.
Methods:
Western blotting was conducted to find out whether RAD001 induced c-Raf-ERK feedback activation and to identify whether RAD001 in combination with c-Raf inhibitor sorafenib could effectively block the feedback activation of c-Raf and downstream proteins. Sulphorhodamine B (SRB) colorimetric assay and colony formation were used to detect the effect of the combination treatment on cell growth and proliferation; finally, the effect on mouse subcutaneous xenografts was examined to confirm the efficacy of the combination treatment in vivo.
Results:
RAD001 effectively inhibited the expressions of mTORC1 and its downstream proteins, and induced the feedback activation of c-Raf. Whereas, RAD001 combined with c-Raf inhibitor sorafenib eliminated RAD001-induced activation of c-Raf-ERK pathway and reversed pancreatic cancer cell resistance to RAD001; compared with the RAD001 alone, sorafenib had a synergistical inhibitory effect with RAD001. And the tumor growth inhibitory effect of the combination was also proved in mouse subcutaneous xenografts in vivo.
Conclusion:
RAD001-induced c-Raf-ERK feedback activation contributes to pancreatic cancer cell resistance to RAD001. Targeting of c-Raf may improve the therapeutic efficacy of RAD001 in patients with pancreatic cancer.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42417855	c-Raf Inhibitor			Price

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