(PQD1) Treatment-emergent resistance to NEDD8-activating enzyme inhibition

描述(申请人提供)：我们将使用NEDD8激活酶(NAE)抑制剂MLN4924测试新的有针对性的策略来调节耐药性的出现和演变。目的1重点评估治疗相关的靶基因突变如何影响自发性疾病模型中的回归和复发。旨在控制已知MLN4924耐药机制的类型和频率的体外策略将与体内治疗相关的复发进行比较，以描绘一种高度单一靶向的药物的选择压力如何推动癌细胞进化。AIM 2测试了一种策略，该策略使用选择性较低的NAE抑制剂，通过提供低水平的二次选择压力来瞬时抑制MLN4924抗性。目的3确定在NAE的已知耐药热点提供不同的选择压力如何影响MLN4924治疗-紧急耐药机制的类型和频率。总的来说，我们使用临床NAE抑制剂MLN4924的研究将为靶向治疗建立新的合理范例，旨在抑制并有可能逆转治疗出现的耐药性。

DESCRIPTION (provided by applicant): 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.