mTOR-mediated metabolic vulnerability of chemotherapy resistant cancer

• Applicant: Dr. Michael Wanzel
• Subject Area: Hematology, Oncology
• Term: from 2017 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 394450860

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 (ICL), which impede replication and transcription and are therefore particularly deleterious. ICL 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), a downstream effector for many oncogenic signaling pathways, is inducing the Fanconi anemia pathway and thereby causing resistance to multiple DNA crosslinking drugs. Similarly, other studies reported deregulated mTOR activity as a cause of resistance to modern targeted therapies.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 deregulated mTOR-signaling in chemoresistant cancer cells limits their potential to compensate metabolite deficiencies by autophagy and thereby renders them vulnerable to metabolically active compounds.Together these observations suggest that mTOR-driven resistance to DNA crosslinking drugs might generate a special metabolic vulnerability that could potentially be exploited for the treatment of cancer patients who have become resistant to classical systemic therapy. In this project, we plan to investigate the mechanism underlying the metabolic vulnerability of chemoresistant cancer cells and explore in preclinical models possible applications in cancer therapy.

• DFG Programme: Research Grants