Nucleophosmin-anaplastic lymphoma kinase-expressing (NPM-ALK+) T cell lymphoma is an aggressive neoplasm. NPM-ALK, an oncogenic tyrosine kinase, plays a critical role in this lymphoma. Recently, selective ALK inhibitors have emerged as a first-line therapy for this neoplasm. Unfortunately, ALK inhibitors were hindered by emergence of resistance and relapse. We have previously demonstrated that type I insulin-like growth factor receptor (IGF-IR) is commonly expressed and activated in this lymphoma. In addition, IGF-IR and NPM-ALK are physically associated and reciprocally enhance their phosphorylation/activation. Herein, we tested the hypothesis that combined inhibition of IGF-IR and NPM-ALK could significantly improve the effects of inhibiting each kinase alone. We used clinically utilized inhibitors of IGF-IR (picropodophyllin; PPP) and ALK (ASP3026) to assess the in vitro cellular effects of combined treatment versus treatment using a single agent. Moreover, we used a systemic NPM-ALK+ T cell lymphoma mouse model to analyze the in vivo effects of PPP and ASP3026 alone or in combination. Our data show that combined treatment with PPP and ASP3026 decreased the viability, proliferation, and anchorage-independent colony formation, and increased apoptosis of NPM-ALK+ T cell lymphoma cells in vitro. The in vitro effects of combined treatment were synergistic and significantly more pronounced than the effects of PPP or ASP3026 alone. Biochemically, simultaneous antagonism of IGF-IR and ALK induced more pronounced decrease in pIGF-IRY1135/1136, pNPM-ALKY646, and pSTAT3Y705 levels than antagonizing IGF-IR or ALK alone. Moreover, combined targeting of IGF-IR and NPM-ALK decreased significantly systemic lymphoma tumor growth and improved mice survival in vivo. Consistent with the in vitro results, the in vivo effects of the combined therapy were more pronounced than the effects of targeting IGF-IR or ALK alone. Combined targeting of IGF-IR and ALK is more effective than targeting IGF-IR or ALK alone in NPM-ALK+ T cell lymphoma. This strategy might also limit emergence of resistance to high doses of ALK inhibitors. Therefore, it could represent a successful therapeutic approach to eradicate this aggressive lymphoma. Importantly, combined inhibition is feasible because of the clinical availability of IGF-IR and ALK inhibitors. Our findings are applicable to other types of cancer where IGF-IR and ALK are simultaneously expressed.

中文翻译：

---

双重抑制 IGF-IR 和 ALK 作为根除 NPM-ALK+ T 细胞淋巴瘤的有效策略。

表达核磷蛋白间变性淋巴瘤激酶 (NPM-ALK+) T 细胞淋巴瘤是一种侵袭性肿瘤。NPM-ALK 是一种致癌性酪氨酸激酶，在这种淋巴瘤中起着关键作用。最近，选择性 ALK 抑制剂已成为这种肿瘤的一线疗法。不幸的是，ALK 抑制剂因出现耐药性和复发而受阻。我们之前已经证明 I 型胰岛素样生长因子受体 (IGF-IR) 在这种淋巴瘤中普遍表达和激活。此外，IGF-IR 和 NPM-ALK 在物理上相关并相互增强它们的磷酸化/激活。在此，我们检验了联合抑制 IGF-IR 和 NPM-ALK 可以显着提高单独抑制每种激酶的效果的假设。我们使用了临床上使用的 IGF-IR 抑制剂（鬼臼苦素；PPP) 和 ALK (ASP3026) 来评估联合治疗与使用单一药物治疗的体外细胞效应。此外，我们使用全身性 NPM-ALK+ T 细胞淋巴瘤小鼠模型来分析 PPP 和 ASP3026 单独或联合使用的体内作用。我们的数据显示，PPP 和 ASP3026 的联合治疗降低了体外 NPM-ALK+ T 细胞淋巴瘤细胞的活力、增殖和不依赖贴壁的集落形成，并增加了细胞凋亡。联合治疗的体外效果是协同的，并且比单独使用 PPP 或 ASP3026 的效果更显着。在生物化学上，与单独拮抗 IGF-IR 或 ALK 相比，同时拮抗 IGF-IR 和 ALK 会导致 pIGF-IRY1135/1136、pNPM-ALKY646 和 pSTAT3Y705 水平更显着降低。而且，IGF-IR 和 NPM-ALK 的联合靶向显着降低了全身性淋巴瘤肿瘤的生长并提高了小鼠体内存活率。与体外结果一致，联合治疗的体内效果比单独靶向 IGF-IR 或 ALK 的效果更明显。在 NPM-ALK+ T 细胞淋巴瘤中，联合靶向 IGF-IR 和 ALK 比单独靶向 IGF-IR 或 ALK 更有效。这种策略也可能限制对高剂量 ALK 抑制剂耐药性的出现。因此，它可以代表根除这种侵袭性淋巴瘤的成功治疗方法。重要的是，由于 IGF-IR 和 ALK 抑制剂的临床可用性，联合抑制是可行的。我们的研究结果适用于同时表达 IGF-IR 和 ALK 的其他类型的癌症。