Understanding tumor addiction to TRK fusions and sensitivity to TRK inhibition

了解肿瘤对 TRK 融合的成瘾性和对 TRK 抑制的敏感性

• 批准号: 10155443
• 负责人: Alexander Drilon
• 金额: $ 62.88万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-18 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10155443
• 关键词: Address; Adult; Aftercare; BRAF gene; Binding; Biology; Biopsy; Cell Line; Chimera organism; Chimeric Proteins; Clinic; Clinical; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Combined Modality Therapy; Complement; DNA Sequence Alteration; Data; Drug resistance; ETV6 gene; Engineering; Gene Expression Profile; Generations; Genomics; Goals; Growth; Histology; Hybrids; In Vitro; Institution; Large Intestine Carcinoma; Lead; Leadership; Learning; Light; MAP Kinase Gene; MEK inhibition; Malignant Neoplasms; Mediating; Mitogen-Activated Protein Kinase Kinases; Modeling; Molecular; Mutation; NIH 3T3 Cells; NTRK1 gene; NTRK2 gene; NTRK3 gene; Neuronal Differentiation; Oncogenic; Pathologist; Pathway interactions; Patients; Pediatric Neoplasm; Pharmaceutical Preparations; Pharmacology; Phosphotransferases; Plasma; Play; Proteins; Proteomics; ROS1 gene; Resistance; Resistance development; Role; Sampling; Scientist; Signal Pathway; Signal Transduction; Solid Neoplasm; Solvents; Therapeutic; Tissues; Tropomyosin; Xenograft procedure; antitumor effect; base; drug sensitivity; exome sequencing; experience; genomic aberrations; improved; in vivo; inhibitor/antagonist; multidisciplinary; neuronal survival; novel; novel therapeutic intervention; objective response rate; pediatric patients; preclinical study; pressure; prevent; receptor; refractory cancer; resistance mechanism; response; screening; targeted treatment; therapy resistant; transcriptome sequencing; transcriptomics; tumor; tumor addiction; tumor progression; tumorigenesis; tumorigenic; vector

NTRK fusions lead to the expression of oncogenic chimeric TRK proteins with constitutively activated kinases, similar to ALK and ROS1 fusions. Most importantly, NTRK fusions are highly actionable in the clinic. First- generation TRK kinase inhibition (larotrectinib) results in rapid and durable histology-agnostic responses, with an objective response rate of 76% across a wide variety of solid tumors (Drilon et al., NEJM, provisionally accepted). Despite these impressive results, little is known about the biology of NTRK fusions, and resistance to 1st-generation therapy ultimately develops. While 2nd-generation inhibitors address on-target resistance, the development of acquired resistance to these drugs likewise represents a challenge. The main objectives of this proposal are to elucidate signaling pathways that mediate the activation and transformative capacity of TRK fusion proteins, and to identify mechanisms of intrinsic or acquired resistance to TRK inhibitors. For this project, we plan to leverage (1) our leadership in ongoing TRK inhibitor clinical trials, (2) our prior experience in identifying and characterizing resistance mechanisms to targeted therapy, and (3) our creation of a multidisciplinary “TRK team” of scientists, pathologists, and clinicians to study TRK biology. In order to shed light on signaling pathways and/or gene expression patterns that mediate TRK fusion kinase activity, we will perform an unbiased global proteomic/transcriptomic screening using patient-derived models treated with 1st- or 2nd-generation TRK inhibitors. Candidate proteins/pathways involved in TRK-mediated tumorigenesis will be validated both genetically and pharmacologically. To determine mechanisms of resistance to 1st-generation (larotrectinib and entrectinib) and 2nd-generation (LOXO-195 and TPX-0005) inhibitors in the clinic, we will perform comprehensive characterization of paired pre- and post-treatment biopsies from patients with NTRK-rearranged solid tumors treated at our institution. Tumors will be characterized by targeted capture-based exome sequencing (MSK-IMPACT), anchored multiplex PCR (MSK Archer Solid Tumor Panel), and pan-TRK IHC; in addition, serial plasma profiling (ddPCR and hybrid capture) will be performed in patients on TRK inhibitor therapy. Building on our prior identification of convergent, on-target resistance (solvent-front mutations), we identified off-target resistance mediated by MAPK pathway reactivation (NRAS/BRAF/GNAS mutations) that may be amenable to combination therapy. For 2nd-generation inhibitor resistance, we have already identified a novel compound NTRK mutation. These efforts will be complemented by the routine creation of NTRK-rearranged patient-derived cell lines and xenografts, and engineered models (transduced primary cell lines/CRISPR-modified). In addition to exploring downstream signaling as previously described, therapeutic strategies will be explored in vitro and in vivo for both on-target resistance (2nd-generation TKI switching), and off-target resistance (combination therapy, e.g. TRK and MEK inhibition). When feasible, candidate strategies will then be explored in the clinic.

NTRK融合导致致癌嵌合TRK蛋白与组成型活化激酶的表达， 类似于ALK和ROS1融合。最重要的是，NTRK融合在诊所中是高度可行的。第一的- 产生的TRK激酶抑制（LAROTROTECTINIB）会导致快速，耐用的组织学反应，并具有 各种实体瘤的客观响应率为76％（Drilon等，NEJM，临时 公认）。尽管有这些令人印象深刻的结果，但对NTRK融合的生物学知之甚少 第一代疗法最终发展。而第二代抑制剂应对靶向抗性的抗性 对这些药物的抗药性的发展同样是一个挑战。 该提案的主要目标是阐明介导激活和的信号通路 TRK融合蛋白的转化能力，并确定固有或获得性的机制 到TRK抑制剂。对于这个项目，我们计划利用（1）我们在正在进行的TRK抑制剂临床试验中的领导才能， （2）我们先前在识别和表征靶向治疗的抗药性机制方面的经验，以及（3） 我们创建了一个由科学家，病理学家和临床医生研究TRK生物学的多学科“ TRK团队”。 为了阐明介导TRK融合激酶的信号通路和/或基因表达模式 活动，我们将使用患者衍生的模型进行公正的全局蛋白质组学/转录组筛查 用第一代或第二代TRK抑制剂处理。 TRK介导的候选蛋白/途径 肿瘤发生将通过遗传和药物验证。 确定对第一代（Larotrectinib和Entertinib）和第二代的抗性机制 （LOXO-195和TPX-0005）诊所的抑制剂，我们将进行配对的全面表征 在我们机构治疗的NTRK重新培养实体瘤患者的治疗前和治疗后活检。 肿瘤将以靶向捕获的外显子组测序（MSK-Impact）为特征，锚定 多重PCR（MSK Archer实体瘤面板）和Pan-Trk IHC；此外，串行等离子体分析（DDPCR） 将在TRK抑制剂治疗的患者中进行杂种捕获）。建立在我们先前确定的基础上 收敛性，靶向抗性（溶剂 - 前突变），我们确定了靶向抗性的抗性 MAPK途径重新激活（NRAS/BRAF/GNA突变）可能适合组合疗法。 对于第二代抑制剂耐药性，我们已经确定了一种新型的化合物NTRK突变。 这些努力将通过常规创建NTRK重新制定的患者衍生细胞系和 Xenographics和工程模型（转导的原始细胞系/CRISPR修饰）。除了探索 如前所述，下游信号传导将在体外和体内探索治疗策略 靶向抗性（第二代TKI开关）和脱靶耐药性（组合疗法，例如 TRK和MEK抑制）。如果可行的话，将在诊所中探索候选策略。

项目成果

Characterization of on-target adverse events caused by TRK inhibitor therapy.

• DOI: 10.1016/j.annonc.2020.05.006
• 发表时间: 2020-09
• 期刊: Annals of oncology : official journal of the European Society for Medical Oncology
• 作者: Liu D;Flory J;Lin A;Offin M;Falcon CJ;Murciano-Goroff YR;Rosen E;Guo R;Basu E;Li BT;Harding JJ;Iyer G;Jhaveri K;Gounder MM;Shukla NN;Roberts SS;Glade-Bender J;Kaplanis L;Schram A;Hyman DM;Drilon A
• 通讯作者: Drilon A

Important Considerations for Real-World Analysis of Neurotrophic Tyrosine Receptor Kinase Fusion Cancer and Tropomyosin Receptor Kinase Inhibitors.

神经营养性酪氨酸受体激酶融合癌和原肌球蛋白受体激酶抑制剂的真实世界分析的重要考虑因素。

• DOI: 10.1200/po.23.00217
• 发表时间: 2023
• 期刊: JCO precision oncology
• 影响因子: 4.6
• 作者: Brose,MarciaS;Hong,DavidS;Drilon,Alexander
• 通讯作者: Drilon,Alexander

Response to Repotrectinib After Development of NTRK Resistance Mutations on First- and Second-Generation TRK Inhibitors.

第一代和第二代 TRK 抑制剂出现 NTRK 耐药突变后对 Repotrectinib 的反应。

• DOI: 10.1200/po.22.00697
• 发表时间: 2023
• 期刊: JCO precision oncology
• 影响因子: 4.6
• 作者: Chen,MonicaF;Yang,Soo-Ryum;Shia,Jinru;Girshman,Jeffrey;Punn,Sippy;Wilhelm,Clare;Kris,MarkG;Cocco,Emiliano;Drilon,Alexander;Raj,Nitya
• 通讯作者: Raj,Nitya

NTRK fusion-positive cancers and TRK inhibitor therapy.

• DOI: 10.1038/s41571-018-0113-0
• 发表时间: 2018-12
• 期刊: Nature reviews. Clinical oncology
• 作者: Cocco E;Scaltriti M;Drilon A
• 通讯作者: Drilon A

Efficacy and Safety of Larotrectinib in Patients With Tropomyosin Receptor Kinase Fusion-Positive Lung Cancers.

• DOI: 10.1200/po.21.00418
• 发表时间: 2022-01
• 期刊: JCO precision oncology
• 影响因子: 4.6
• 作者: Drilon A;Tan DSW;Lassen UN;Leyvraz S;Liu Y;Patel JD;Rosen L;Solomon B;Norenberg R;Dima L;Brega N;Shen L;Moreno V;Kummar S;Lin JJ
• 通讯作者: Lin JJ