mTORC1 and MAPK Inhibitors for Treatment of Cancer

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Rapamycin is a macrolide antibiotic used as an immunosuppressant to prevent organ rejection in transplant patients. Rapamycin and analogues have also been found to have anti-proliferative properties and their effects have been studied in a variety of cancers. Despite early promise, however, clinical tests have proved less successful than had been hoped.
Rapamycin

Rapamycin

PD0325901A report in the Journal of Clinical Investigation now suggests a reason for this lack of success. The anti-tumour effects of rapamycin are brought about by inhibition of the mTORC1 (mammalian target of rapamycin complex 1) pathway which is activated in many cancers, but the new study shows that this inhibition leads to activation of the mitogen-activated protein kinase(MAPK) cascade which stimulates the growth of cancer cells. The authors showed that the MAPK inhibitor, PD0325901, enhanced the effect of rapamycin or an analogue, RAD001 in cancer cell lines, and a xenograft mouse model of cancer.

The results suggest that patient stratification based on molecular pathways and combined use of these drug families, both of which are currently used as single agents in the clinic, will provide more effective treatments for cancer.

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