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. 2020 Nov 16;11:562505. doi: 10.3389/fendo.2020.562505

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Copyright © 2020 Zanini, Renzi, Giovinazzo and Bermano.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Proposed mechanisms for resistance to Rapalogues in NET. 1- Inhibition of mTOR results in PI3k-Akt-mTOR pathway reactivation and MAPK pathway activation. 2- Inactivating mutations in TSC1/2 cause the inactivation of the TSC1/TSC2 protein complex leading to mTOR hyperactivation. 3- mTOR inhibitor treatment cause an increase in tyrosine kinase receptors and growth factor secretion. 4- GSK3 over-expression accompanied by the decrease of IRS-1 protein leads to decreased autophagy and cell resistance to Everolimus. 5- The up-regulation of angiogenic factors mTOR-independent or the re-expression of HIFα.