Mechanisms of resistance to ALK inhibitors in ALK-rearranged lymphoma

 描述（由申请方提供）：间变性淋巴瘤激酶（ALK）是一种有效的癌症相关亚组的驱动癌基因，包括间变性大细胞淋巴瘤（ALCL）、非小细胞肺癌（NSCLC）、炎性肌纤维母细胞瘤（IMT）和神经母细胞瘤。第一代和第二代ALK酪氨酸激酶抑制剂（TKI）的最新开发和FDA批准彻底改变了治疗ALK驱动的癌症的治疗机会。在NSCLC中，TKI抑制剂对此类肿瘤具有显著的临床疗效，但由于肿瘤细胞产生TKI耐药性，因此在8-10个月的时间窗后效果丧失。已经阐明或提出了TKI耐药NSCLC的几种耐药分子机制，包括ALK突变、扩增或其他酪氨酸激酶的旁路信号传导。对耐药机制的阐明可以指导复发患者的额外治疗。与NSCLC相比，ALCL中TKI的临床研究处于非常早期的阶段，耐药机制几乎完全未知。在本项目中，我们旨在对ALCL中产生ALK TKI耐药的分子机制进行全面表征。通过假设驱动或筛选方法，我们将阐明大多数耐药机制，并将在临床前研究中评估可专门用于每种机制的其他治疗策略。具体而言，我们将生成一个全面的ALK突变目录，这些突变赋予对TKI的耐药性及其对不同ALK抑制剂的敏感性。我们将针对因ALK扩增或PI 3 K上调而耐药的患者验证并提出治疗方案。最后，我们将使用蛋白质组学和遗传筛选来发现新的抗性机制。因此，我们的研究结果将为ALK TKI耐药的淋巴瘤患者的治疗管理提供实验指导。

 DESCRIPTION (provided by applicant): The Anaplastic Lymphoma Kinase (ALK) is a potent driver oncogene for a relevant subset of cancers, including Anaplastic Large Cell Lymphoma (ALCL), Non Small Cell Lung Cancer (NSCLC), Inflammatory Myofibroblastic tumors (IMT) and neuroblastoma. The recent development and FDA approval of first and second-generation ALK tyrosine kinase inhibitors (TKI) has revolutionized the therapeutic opportunities to treat ALK-driven cancers. In NSCLC TKI inhibitor have dramatic clinical efficacy on such tumors, but the effect is lost after a window of time of 8-10 months because of the development of TKI resistance by the tumor cells. Several molecular mechanisms of resistance have been elucidated or proposed for TKI resistant NSCLC, including ALK mutation, amplifications, or by-pass signaling by other tyrosine kinases. The elucidation of the mechanisms of resistance can dictate additional lines of therapies in relapsing patients. In contrast to NSCLC, in ALCL the clinical studies with TKI are at a very early stage and mechanisms of resistance are almost completely unknown. In this project, we aim at generating a comprehensive characterization of the molecular mechanisms that generate resistance to ALK TKI in ALCL. By hypothesis-driven or screening approaches, we will elucidate most of the resistance mechanisms and we will evaluate in pre-clinical studies additional therapeutic strategies that could be specifically used for each mechanism. Specifically, we will generate a comprehensive catalog of ALK mutations that confer resistance to TKI and their sensitivity to different ALK inhibitors. We will validate ad propose therapies for patients that become resistant by ALK amplification or PI3K upregulation. Finally we will use proteomic and genetic screens to discover novel mechanisms of resistance. Thus, our results will provide an experimental guide for the therapeutic management of lymphoma patients that develop resistance to ALK TKI.