Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer

Arkaitz, C. et al., J. Clin. Invest. 118:3065–3074 (2008)

Speaker: Yu-Hong Chen (陳俞宏)                          Time: 13:00~14:00, Nov. 12, 2008

Commentator: Dr. Pei-Jung Lu (呂佩融博士)                Place: Room 601

Abstract:

The mammalian target of rapamycin (mTOR) was involved in cell growth and proliferation. In human cancer cells, aberrant mTOR activation was correlated with tumorigenesis which has been a potential therapeutic target. In insulin/IGF signaling pathway, mutation of PTEN results in excess activation of Akt, mTOR, S6K and eIF-4E and cause several types of tumors. Recently studies demonstrated that mTOR signals through 2 complexes, mTORC1 and mTORC2. Rapamycin, a macrolide antibiotic produced by Streptomyces hygroscopicus, which acts selectively on mTORC1 complex and inhibit it to block the progression of malignancies. Surprisingly, immunohistochemical analysis of tumor samples from rapamycin analog RAD001-treated patients identified a robust activation of the MAPK pathway. Similarly, RAD001 treatment produced a significant increase of ERK phosphorylation in Pten-null mouse prostates in which mTORC1 was inhibited. Tuberous sclerosis complex (TSC1 and TSC2) are the protein found in patient with tuberous sclerosis that regulate S6K1 and 4EBP1 by inhibiting mTORC1. The results show that rapamycin and its analogs activate the MAPK pathway, in what represents a novel mTORC1-MAPK feedback loop. Furthermore, the authors identify the ability of MEK1/2 and mTORC1 inhibitor had an additive effect to inhibit cell growth. Ultimately, they tested the cooperativity of RAD001 and PD0325901 to prove that the combination therapy led to mTORC1 inhibition with concomitant abrogation of MAPK feedback. Moreover, the data show this therapy not only decreased cell proliferation but also elevated levels of apoptosis. Together these results provide a novel molecular basis for patient stratification and combinatorial use of mTORC1 and MAPK inhibitors for the treatment of cancer.

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