The Latest in LAM Science: Lost in translation: a neglected mTOR target for lymphangioleiomyomatosis

LAM is caused by changes in some genes that control cell growth called the mTORC1 pathway. Cells use this pathway to make many copies of proteins needed for growth from an mRNA template, a process termed mRNA translation, in much the same way as a printing press makes lots of newspapers. The title´Lost in Translation’ of the paper published in Eur Respir Rev 2023; 32: 230100 [DOI: 10.1183/16000617.0100-2023] refers to the fact that LAM cells have lost full control of mRNA translation-sort of a runaway printing press. The mTORC1 pathway controls the protein printing press by activating molecular switches in either the S6K1/S6 pathway, or the 4E-BP1/eIF4E pathway. One of the co-authors of this article, namely Professor Nahum Sonenberg, discovered the protein eIF4E several decades ago (and became one of the most frequently cited scientists of all time). Rapamycin (Sirolimus), can turn off the S6K1/S6 switch for protein production but not the 4E-BP1/eIF4E switch, which results in continued signaling for growth. In the ‘Lost’ article, the authors suggest that an approach to block both protein production pathways, S6K1/S6 and 4E-BP1/eIF4E, would be a better approach to preventing LAM cell growth. Proteins made by 4E-BP1/eIF4E pathway are particularly important for the survival of stem cells, which are self-renewing cells that generate a lot of additional, lung damaging LAM cells.  Cancer researchers have been investigating ways to control and destroy stem cells for a long time, and the LAM community can learn from their discoveries.  One strategy these investigators have used is to link  S6K1/S6 inhibitors and 4EBP1/eIF4E inhibitors together to create composite compounds called bi-steric mTORC1 inhibitors, which are now being studied ‘first in man’ Phase 1 cancer trials. These studies are designed to determine if the drugs are both effective against the cancer stem cell growth and also tolerated well by cancer patients. The hope is that we can find a bi-steric inhibitor that has a risk/benefit profile that is appropriate for LAM patients, who generally have a more favorable prognosis than the cancer patients the drugs are now being studied in, and therefore a different perspective on what constitutes an acceptable side effect profile. In the meantime, LAM researchers continue to work hard to understand the complex cell mechanisms that control mTORC1 pathways in LAM lungs, which will be required to design remission inducing LAM therapies.

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