It seems like a paradox that, of all things, a molecule which renders tumors resistant to cancer medications also suppresses a mechanism that is vital for the survival of tumor cells. This is what Professor Thorsten Stiewe, DZL scientist, and his colleagues report in Nature Communications.
Chemotherapies and what is referred to as targeted cancer therapies, which specifically address growth-stimulating tumor characteristics, have substantially improved over the past few decades. However, they still fail in almost half of all tumor patients since cancer cells are very versatile and can change in such a way that they become resistant to the medication administered. Hence, the tumor comes back or treatment does not work at all. The molecule mTOR (mechanistic target of rapamycin) kinase plays a key role in developing resistance. Previously administered agents directly inhibiting mTOR, however, were either hardly effective or associated with severe side effects. Researchers in the team of Marburg-based DZL scientist professor Thorsten Stiewe have found a mechanism which might allow the breaking of resistant cancer cells through mTORC1.
mTOR is a vital control center in cells and exists in the form of two different protein complexes, mTORC1 and mTORC2. They react to many environmental factors, e.g. growth factors or nutrient status, to control cell growth and cell metabolism. In a growth-promoting environment, mTOR stimulates cell metabolism leading to an increased production of proteins, lipids, and nucleotides while degrading processes are inhibited. This also includes autophagy. Here, cells transport substances to the interior of the cell, dissect, and then recycle them.
Professor Thorsten Stiewe and his colleagues have been able to show that autophagy is vital for the survival of therapy-resistant tumor cells since it is this mechanism that helps them deal with any metabolic disturbances caused by cancer medications. Furthermore, they found that a permanent activation of mTORC1 inhibits autophagy. In the absence of autophagy, the metabolism of resistant cancer cells becomes vulnerable again, so the relevant medication can trigger an energy crisis ultimately resulting in programmed cell death. Consequently, substances which persistently activate mTORC1 and hence inhibit autophagy are a promising new approach for patients whose tumor resistance is dependent on mTOR.
mTOR-mediated cancer drug resistance suppresses autophagy and generates a druggable metabolic vulnerability. Gremke N, Polo P, Dort A, Schneikert J, Elmshäuser S, Brehm C, Klingmüller U, Schmitt A, Reinhardt HC, Timofeev O, Wanzel M, Stiewe T. Nat Commun. 2020 Sep 17;11(1):4684. DOI: 10.1038/s41467-020-18504-7.