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

描述（由申请人提供）：我们将测试使用nedd8活化酶（NAE）抑制剂MLN4924调节耐药出现和进化的新型靶向策略。目的1侧重于评估治疗相关的靶突变如何影响自发性疾病模型中的消退和复发。设计用于控制已知mln4924耐药机制类型和频率的离体策略将与体内治疗相关的复发进行比较，以描述强单靶向药物的选择压力如何驱动癌细胞进化。目的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性压力来短暂抑制MLN4924耐药性。目的3确定在NAE中已知的耐药热点提供不同的选择压力如何影响MLN4924治疗产生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，旨在抑制和潜在地逆转治疗中出现的耐药性。

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.