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Wanzel Group

mTOR-mediated metabolic vulnerability of chemotherapy-resistant cancer

The success of cancer therapy is limited by the development of resistance to systemic therapy approaches. Among the most widely used anti-cancer drugs are the platinum compounds such as cisplatin. The cytotoxic activity of these compounds is dependent on their ability to induce DNA interstrand crosslinks, which impede replication and transcription and are therefore particularly deleterious. Interstrand crosslinks can only be resolved with the help of the Fanconi anemia DNA repair pathway. In our previous studies on lung adenocarcinoma we have observed that the mammalian (or mechanistic) target of rapamycin (mTOR) is inducing the Fanconi pathway and thereby causing resistance to multiple DNA crosslinking drugs. As mTOR functions as a downstream effector for many frequently mutated oncogenic pathways, mTOR signaling is found to be hyperactive in a high percentage of human cancers.

To identify new treatment approaches for cancer cells that have become chemotherapy-resistant because of mTOR-stimulated DNA repair, we screened DNA crosslinker-resistant tumor cell lines for vulnerabilities and observed a remarkable hypersensitivity to 2-deoxyglucose (2DG) and dichloroacetate (DCA). These two compounds are considered to interfere with special metabolic requirements of cancer cells that are often referred to as the Warburg effect and represent one of the new hallmarks of cancer. In general, it can be assumed that metabolite deficiencies caused by metabolically active compounds could be resolved by self-digestion (autophagy) as a survival mechanism. Preliminary results indicate that mTOR-induced autophagy defects in chemo-resistant cancer cells might cause their metabolic hypersensitivity.

Together these observations suggest that mTOR-driven resistance to DNA damaging drugs might generate a special metabolic vulnerability that could potentially be exploited for treatment of cancer patients that have become resistant to classical chemotherapeutics. In this project we plan to investigate the mechanism underlying the metabolic hypersensitivity of chemo-resistant cancer cells and explore in preclinical models possible applications in cancer therapy.

DFG WA 2725/2-1