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Inhibition of the mechanistic target of rapamycin induces cell survival via MAPK in tuberous sclerosis complex. | LitMetric

Inhibition of the mechanistic target of rapamycin induces cell survival via MAPK in tuberous sclerosis complex.

Orphanet J Rare Dis

Department of Internal Medicine, Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati College of Medicine, 231 Albert Sabin Way-ML 0564, Cincinnati, OH, 45267, USA.

Published: August 2020

AI Article Synopsis

Article Abstract

Background: Tuberous sclerosis complex (TSC) is a genetic disorder that cause tumors to form in many organs. These lesions may lead to epilepsy, autism, developmental delay, renal, and pulmonary failure. Loss of function mutations in TSC1 and TSC2 genes by aberrant activation of the mechanistic target of rapamycin (mTORC1) signaling pathway are the known causes of TSC. Therefore, targeting mTORC1 becomes a most available therapeutic strategy for TSC. Although mTORC1 inhibitor rapamycin and Rapalogs have demonstrated exciting results in the recent clinical trials, however, tumors rebound and upon the discontinuation of the mTORC1 inhibition. Thus, understanding the underlying molecular mechanisms responsible for rapamycin-induced cell survival becomes an urgent need. Identification of additional molecular targets and development more effective remission-inducing therapeutic strategies are necessary for TSC patients.

Results: We have discovered an Mitogen-activated protein kinase (MAPK)-evoked positive feedback loop that dampens the efficacy of mTORC1 inhibition. Mechanistically, mTORC1 inhibition increased MEK1-dependent activation of MAPK in TSC-deficient cells. Pharmacological inhibition of MAPK abrogated this feedback loop activation. Importantly, the combinatorial inhibition of mTORC1 and MAPK induces the death of TSC2-deficient cells.

Conclusions: Our results provide a rationale for dual targeting of mTORC1 and MAPK pathways in TSC and other mTORC1 hyperactive neoplasm.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7433150PMC
http://dx.doi.org/10.1186/s13023-020-01490-wDOI Listing

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