We will test novel targeted strategies to modulate the emergence and evolution of drug resistance using the NEDD8-activating enzyme (NAE) inhibitor MLN4924.
Aim 1 focuses on evaluating how treatment-associated on-target mutations influence regression and relapse in spontaneous disease models. Ex-vivo strategies designed to control the types and frequencies of known MLN4924-resistance mechanisms will be compared to in vivo treatment-associated relapse to delineate how selective pressure by a strongly mono-targeted drug drives cancer cell evolution.
Aim 2 tests a strategy that uses a less selective NAE inhibitor to transiently suppress MLN4924 resistance by providing a low level, secondary selective pressure.
Aim 3 determines how providing distinct selective pressures at a known drug resistance hotspot in NAE influence the type and frequency of MLN4924 treatment-emergent resistance mechanisms. Collectively, our studies using the clinical NAE inhibitor MLN4924 will establish new rational paradigms for targeted therapies designed to suppress and potentially reverse treatment-emergent drug resistance.
The NEDD8-activating enzyme inhibitor has recently begun testing in humans for hematological and advanced non-hematological malignancies. In this R01 application, we propose new investigations into molecular mechanisms of treatment-emergent resistance during MLN4924 therapy and devise innovative strategies to overcome these to restore the drug's anti-cancer efficacy.
| Wei, Yang; Toth, Julia I; Blanco, Gabrielle A et al. (2018) Adapted ATPase domain communication overcomes the cytotoxicity of p97 inhibitors. J Biol Chem 293:20169-20180 |
| Her, Nam-Gu; Toth, Julia I; Ma, Chen-Ting et al. (2016) p97 Composition Changes Caused by Allosteric Inhibition Are Suppressed by an On-Target Mechanism that Increases the Enzyme's ATPase Activity. Cell Chem Biol 23:517-28 |
