Mechanisms of resistance to ALK inhibitors in ALK-rearranged lymphoma

摘要 T细胞淋巴瘤(TCL)的一种特殊亚型称为间变性大细胞淋巴瘤(ALCL) 涉及间变性淋巴瘤激酶(ALK)基因的染色体易位。化疗是最好的 目前ALK+ALCL的治疗标准，但在大约30%的患者中失败。大多数失败的ALK+ALCL 化疗对碱性磷酸酶酪氨酸激酶抑制剂(TKI)有很好的反应，如Crizotinib，具有更高的 儿童的反应比成人的反应更好，FDA机构最近批准了突破性的治疗指定 用于治疗复发/难治性ALK+ALCL的患者。基于这些令人兴奋的结果， 认为未来ALK TKIs将成为ALCL的一线治疗并不是不可能的，因此 克服化疗的长期毒性。类似的转换也发生在ALK+非 目前ALK TKIs一线治疗的小细胞肺癌(NSCLC)。 尽管大多数ALK+ALCL患者对化疗无效，但经联合治疗后完全缓解 ALK TKIs，仍有一小部分患者迅速产生耐药性。此外，应答者患者不是 完全治愈，因为停用克里佐替尼与淋巴瘤迅速复发有关，即使在多次 多年来完全缓解，疾病检测不出来。因此，AlCL可以发展分子机制。 保护淋巴瘤细胞不受ALK TKI活性的影响。实现治疗ALK+的雄心勃勃的目标 ALCL尽量用靶向治疗和替代化疗，有必要彻底 了解这些导致ALCL中ALK TKI耐药的机制。 通过基因筛选、广泛的测序和小鼠模型，我们确定了三种主要机制 导致ALK TKI耐药，并可能维持ALCL细胞的长期持久性：-我们鉴定了一种 当我们发现PTPN1和PTPN2是碱性磷酸酶时的磷酸酶介导的机制 并与SHP2磷酸酶一起调节ALCL细胞对ALK TKIs的敏感性；-我们发现 激活PI3Kγ信号支持在碱性磷酸酶抑制期间周围细胞的存活；-我们阐明了 Rho家族GTP酶在ALCL中介导ALK信号的关键作用。对于这个项目，我们假设 针对这三条主要途径进行特定的联合治疗可能会应对耐药性并导致 根治ALK+ALCL根治永存细胞。在这个项目中，我们将验证这一概念 体外和体内模型将被用来测试不同的治疗策略。因此，AlK+AlCL可以 成为第一个无需化疗即可完全治愈的T细胞淋巴瘤，具有明显的远期 为受这种疾病影响的儿童和成人提供福利。此外，我们的结果可能会为扩大 这些治疗理念适用于其他不治之症的TCL。

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.