Predicting sensitivity and resistance in RET-driven cancers

Selpercatinib(LOXO-292)是一种高活性的选择性RET抑制剂，正在进行注册研究 RET依赖型癌症的计划(libretto-001阶段1/2试验)(美国FDA于2020年批准RET 融合阳性肺癌/甲状腺癌和RET突变甲状腺癌)。不幸的是，抵抗是 没有特征，仍然是一种负担。本提案通过确定以下内容来预测和解决这一未得到满足的需求 以及内在和获得性基因组和非基因组抗性的功能表征机制 RET依赖癌症中的选择性RET抑制。为了实现这一目标，我们将利用独特的临床、 我们可以使用计算和翻译资源。目标1将确定内在因素的决定因素 依赖RET的癌症患者对RET抑制的抵抗。赛培卡替尼应答者的治疗前活检 而无反应者将接受靶向/整个外显子组测序。计算分析将探索 克隆性、等位基因不平衡和共突变特征与Selpercatinib反应和 无进展生存。目标2将建立对选择性RET的获得性耐药机制 抑制力。配对治疗前后肿瘤活检和纵向无细胞(Cf)DNA (基线、治疗中、进展中/进展后)将对libretto-001患者的情况进行分析。利用配对 样本将允许识别紧急基因组和非基因组(包括组织学/EMT 转化)抗性机制。此外，血浆分析将允许动态评估 赛培卡替尼抵抗，捕捉到一系列基因组进化的后果。Aim 3将在功能上 表征对选择性RET抑制的抗性。独特而丰富的患者衍生模型库 治疗-对RET耐药和RET抑制剂耐药的RET依赖癌症将因正在进行的前瞻性研究而增加 从libretto-001和商业用途收集和模型开发。在这些模型中，目标是 (继发性RET突变)和脱靶(MET/PI3K/KRAS/MDM2激活)抗性机制将是 根据细胞/肿瘤活性、受体酪氨酸激酶激活和下游的功能表征 信令依赖关系。新的治疗策略，特别是RET酪氨酸激酶抑制物类型转换 (靶上抵抗)和联合治疗(靶外抵抗)，将在体外和体内进行探索。 然后，最佳组合疗法将被用于同情使用计划，以确认他们的 并为患者提供量身定做的挽救生命的治疗。此外，符合目标的患者 耐药性将按照协议(Drilon PI)使用下一代RET抑制剂TPX-0046进行治疗。这 考虑到大约400名患者已经接受了治疗，这项提议既有直接意义，也有长期意义 塞培卡替尼在世界各地处于试验阶段，该药物可能获得批准并迅速通过 多个监管机构。这些当前和未来的患者迫切需要策略来重建 选择性RET抑制进展后的持久疾病控制。

Selpercatinib (LOXO-292) is a highly active selective RET inhibitor explored on an ongoing registrational program (LIBRETTO-001 phase 1/2 trial) in RET-dependent cancers (US FDA approval in 2020 for RET fusion-positive lung/thyroid cancer and RET-mutant thyroid cancer). Unfortunately, resistance is uncharacterized and remains a liability. This proposal anticipates and addresses this unmet need by identifying and functionally characterizing mechanisms of intrinsic and acquired genomic and non-genomic resistance to selective RET inhibition in RET-dependent cancers. To accomplish this, we will leverage unique clinical, computational, and translational resources at our disposal. Aim 1 will identify determinants of intrinsic resistance to RET inhibition in RET-dependent cancers. Pre-treatment biopsies of selpercatinib responders and non-responders will undergo targeted/whole exome sequencing. Computational analysis will explore the role of clonality, allelic imbalance, and co-mutational signatures relative to selpercatinib response and progression-free survival. Aim 2 will establish the mechanisms of acquired resistance to selective RET inhibition. Paired pre-treatment and post-progression tumor biopsies and longitudinal cell-free (cf)DNA (baseline, on-treatment, at/post- progression) from LIBRETTO-001 patients will be profiled. Utilizing paired samples will allow for the identification of emergent genomic and non-genomic (including histologic/EMT transformation) resistance mechanisms. In addition, plasma profiling will allow for a dynamic assessment of selpercatinib resistance that captures the consequences of serial genomic evolution. Aim 3 will functionally characterize resistance to selective RET inhibition. A unique and rich library of patient-derived models of treatment-naïve and RET inhibitor resistant RET-dependent cancers will be augmented by ongoing prospective collection and model development from LIBRETTO-001 and commercial use. In these models, on-target (secondary RET mutations) and off-target (MET/PI3K/KRAS/MDM2 activation) resistance mechanisms will be functionally characterized in terms of cell/tumor viability, receptor tyrosine kinase activation, and downstream signaling dependencies. Novel therapeutic strategies, specifically RET tyrosine kinase inhibitor type switching (on-target resistance) and combinatorial therapies (off-target resistance), will be explored in vitro and in vivo. Optimal combination therapies will then be employed in compassionate use programs to confirm their effectiveness and provide tailored, life-saving treatment to patients. In addition, patients with on-target resistance will be treated on-protocol (Drilon PI) with the next-generation RET inhibitor, TPX-0046. This proposal has both immediate and long-term relevance considering that about 400 patients have been treated with selpercatinib around the world on trial and the potential approval and rapid adoption of this drug by multiple regulatory agencies. These current and future patients are in dire need of strategies to re-establish durable disease control after progression on selective RET inhibition.