Mechanisms of resistance to ALK inhibitors in ALK-rearranged lymphoma

ALK 重排淋巴瘤对 ALK 抑制剂的耐药机制

• 批准号: 10371035
• 负责人: Roberto Chiarle
• 金额: $ 41.2万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-16 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10371035
• 关键词: 3-Dimensional; ALK gene; Adult; Affect; Biology; CCL19 gene; Cancer Patient; Candidate Disease Gene; Cells; Child; Chromosomal Rearrangement; Chromosomal translocation; Clinical; Combined Modality Therapy; Disease; Disease remission; Down-Regulation; FDA approved; Family; Future; Generations; Genetic Screening; Genetic Status; Goals; Grant; Guanosine Triphosphate Phosphohydrolases; In Vitro; Ki-1 Large-Cell Lymphoma; Lead; Lymphoma; Lymphoma cell; Lymphomagenesis; MAP Kinase Gene; Mediating; Modality; Modeling; Molecular; Mus; Mutate; Mutation; Non-Small-Cell Lung Carcinoma; PTPN1 gene; PTPN11 gene; Pathway interactions; Patients; Pattern; Phase I/II Clinical Trial; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Recurrence; Refractory; Relapse; Resistance; Resistance development; Role; Secondary to; Signal Pathway; Signal Transduction; T-Cell Lymphoma; T-Lymphocyte Subsets; Testing; Therapeutic; Toxicity due to chemotherapy; Tyrosine Kinase Inhibitor; anaplastic lymphoma kinase; base; chemokine receptor; chemotherapy; crizotinib; experimental study; improved; in vivo; in vivo Model; inhibitor therapy; kinase inhibitor; mouse model; novel; novel therapeutic intervention; partial response; prevent; resistance mechanism; response; rho; standard of care; success; targeted treatment; young adult

ABSTRACT A specific subset of T cell lymphoma (TCL) called Anaplastic Large Cell Lymphoma (ALCL) frequently harbors chromosomal translocations involving the Anaplastic Lymphoma Kinase (ALK) gene. Chemotherapy is the current standard of care for ALK+ ALCL, but fails in approximately 30% of patients. Most ALK+ ALCL that fail chemotherapy respond well to the ALK tyrosine kinase inhibitors (TKIs), such as crizotinib, with higher responses in children than in adults and FDA agency recently granted the breakthrough therapy designation for crizotinib for the treatment of patients with relapsed/refractory ALK+ ALCL. Based on these exciting results, it is not impossible to think that in the future ALK TKIs will become the first-line therapy for ALCL, thus overcoming the long-term toxicity of chemotherapy. A similar switch has happened in the case of ALK+ non- small cell lung cancer (NSCLC) that is currently treated in first-line with ALK TKIs. Despite most ALK+ ALCL patients refractory to chemotherapy achieve complete remission when treated with ALK TKIs, still a fraction of patients quickly develop resistance. In addition, responder patients are not completely cured as discontinuation of crizotinib is associated with rapid lymphoma relapse even after many years of complete remission with undetectable disease. Therefore, ALCL can develop molecular mechanisms that protect lymphoma cells from the activity of ALK TKIs. To achieve the ambitious goal of treating ALK+ ALCL with targeted therapy and replace chemotherapy as much as possible, there is need to completely understand these mechanisms that lead to ALK TKI resistance in ALCL. By genetic screenings, extensive sequencing and mouse models, we identified three main mechanisms leading to ALK TKI resistance and possibly sustaining the long-term persistence of ALCL cells: - we identified a phosphatase-mediated mechanism when we discovered that PTPN1 and PTPN2 are phosphatases of ALK and together with the SHP2 phosphatase regulate the sensitivity of ALCL cells to ALK TKIs; - we discovered that activation of PI3Kγ signaling supports survival of persister cells during ALK inhibition; - we elucidated the key role of the Rho family GTPases to mediate ALK signaling in ALCL. For this project, we hypothesize that targeting these three main pathways with specific combined therapies could cope with resistance and lead to the eradication of persister cells for a complete cure of ALK+ ALCL. In this project, we will validate this concept with in vitro and in vivo models that will be used to test different therapeutic strategies. Thus, ALK+ ALCL could become the first T cell lymphoma to be completely cured without chemotherapy, with obvious long-term benefits for children and adults affected by this disease. In addition, our results could pave the way to broaden these therapeutic concepts to other incurable TCL.

摘要 一种称为间变性大细胞淋巴瘤（ALCL）的T细胞淋巴瘤（TCL）的特定亚群经常携带 涉及间变性淋巴瘤激酶（ALK）基因的染色体易位。化疗是 目前ALK+ ALCL的标准治疗，但在约30%的患者中失败。大多数ALK+ ALCL失败 化疗对ALK酪氨酸激酶抑制剂（TKI）如克唑替尼反应良好， 儿童的反应比成人好，FDA最近批准了突破性治疗指定 克唑替尼治疗复发性/难治性ALK+ ALCL患者。基于这些令人兴奋的结果， 认为未来ALK TKI将成为ALCL的一线治疗并非不可能，因此 克服化疗的长期毒性。类似的转换发生在ALK+非 小细胞肺癌（NSCLC），目前正在使用ALK TKI进行一线治疗。 尽管大多数化疗难治性ALK+ ALCL患者在接受 ALK TKI，仍然有一小部分患者迅速产生耐药性。此外，应答患者 完全治愈，因为即使经过多次治疗，停用克唑替尼仍与淋巴瘤快速复发有关 年完全缓解，无法检测到疾病。因此，ALCL可以发展分子机制 保护淋巴瘤细胞免受ALK TKI活性的影响。实现治疗ALK+的宏伟目标 ALCL用靶向治疗并尽可能替代化疗，有必要彻底 了解导致ALCL中ALK TKI耐药的这些机制。 通过基因筛选、广泛测序和小鼠模型，我们确定了三个主要机制， 导致ALK TKI耐药，并可能维持ALCL细胞的长期存在：-我们发现了一种 当我们发现PTPN 1和PTPN 2是ALK的磷酸酶时， 并与SHP 2磷酸酶一起调节ALCL细胞对ALK TKI的敏感性; -我们发现 PI 3 K γ信号的激活支持ALK抑制期间持续细胞的存活; -我们阐明了 Rho家族GTP酶在ALCL中介导ALK信号传导的关键作用。对于这个项目，我们假设， 针对这三个主要途径的特定联合疗法可以科普耐药性， 根除持续存在的细胞以完全治愈ALK+ ALCL。在本项目中，我们将验证这一概念 用体外和体内模型来测试不同的治疗策略。因此，ALK+ ALCL可以 成为第一个不用化疗就能完全治愈的T细胞淋巴瘤， 对受这种疾病影响的儿童和成人的好处。此外，我们的研究结果可以为扩大 将这些治疗理念应用于其他无法治愈的TCL。