Mechanistic Target of Rapamycin (mTOR) is a highly conserved serine/thereonine protein kinase that plays a crucial role as part of two distinct kinase complexes, mTOR1C and mTOR2C, to regulate cell growth and metabolism. Abnormal activation of mTOR has been implicated in the pathogenesis of several cancers, type 2 diabetes, obesity, and neurodegeneration. Numerous mTOR kinase inhibitors are currently in development with several currently be evaluated as anticancer therapy in clinical trials. However, given recent clinical experience with target therapeutics, acquired drug resistance in mTOR is thought to be very likely.
Rutgers scientists have developed a diagnostic assay to identify patients that may become resistant to mTOR kinase inhibitors. They successfully identified a hotspot in the drug-binding site of mTOR kinase - L2185. When L2185 is mutated to ‘A’ or ‘C’ at the genomic locus of cancer cells, resistance to a large number of mTOR kinase inhibitors arises, rendering drug-refractory cancer growth. In vivo experiments demonstrated that xenograft colorectal tumors carrying the L2185 mutant mTOR exhibited resistance to an mTOR kinase inhibitor in mice, whereas the WT control tumors’ growth was strongly attenuated. Thus, the L2185 mutations hold the promise to be used as biomarkers for clinical diagnosis of drug resistance to mTOR kinase inhibitors.
- Companion diagnostic assay to predict patients’ response for mTOR kinase inhibitor drugs
- Diagnostic assay to identify eligible patients and improve response rates in clinical trials for mTOR kinase inhibitor drugs
- Monitor the potential occurrence of drug resistance in patients
- Isogenic cancer cell lines and yeast strains expressing wild type and drug-resistant mTOR alleles for drug development and evaluation
- The assay is simple, timely, and highly cost effective
- It can potentially improve patient outcomes and facilitate the development of personalized therapy
- Valuable assays for developing second generation of mTOR kinase inhibitors refractory to drug-resistant mutations
Intellectual Property & Development Status:
Patent pending. Available for licensing and/or research collaboration.