Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino 10126, Italy.
Dana Farber Cancer Institute, Boston, MA 02115, USA.
Sci Transl Med. 2023 Jun 28;15(702):eabo3826. doi: 10.1126/scitranslmed.abo3826.
Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) show potent efficacy in several ALK-driven tumors, but the development of resistance limits their long-term clinical impact. Although resistance mechanisms have been studied extensively in ALK-driven non-small cell lung cancer, they are poorly understood in ALK-driven anaplastic large cell lymphoma (ALCL). Here, we identify a survival pathway supported by the tumor microenvironment that activates phosphatidylinositol 3-kinase γ (PI3K-γ) signaling through the C-C motif chemokine receptor 7 (CCR7). We found increased PI3K signaling in patients and ALCL cell lines resistant to ALK TKIs. PI3Kγ expression was predictive of a lack of response to ALK TKI in patients with ALCL. Expression of CCR7, PI3Kγ, and PI3Kδ were up-regulated during ALK or STAT3 inhibition or degradation and a constitutively active PI3Kγ isoform cooperated with oncogenic ALK to accelerate lymphomagenesis in mice. In a three-dimensional microfluidic chip, endothelial cells that produce the CCR7 ligands CCL19/CCL21 protected ALCL cells from apoptosis induced by crizotinib. The PI3Kγ/δ inhibitor duvelisib potentiated crizotinib activity against ALCL lines and patient-derived xenografts. Furthermore, genetic deletion of CCR7 blocked the central nervous system dissemination and perivascular growth of ALCL in mice treated with crizotinib. Thus, blockade of PI3Kγ or CCR7 signaling together with ALK TKI treatment reduces primary resistance and the survival of persister lymphoma cells in ALCL.
间变性淋巴瘤激酶（ALK）酪氨酸激酶抑制剂（TKI）在几种ALK 驱动的肿瘤中显示出强大的疗效，但耐药性的发展限制了它们的长期临床影响。虽然在ALK 驱动的非小细胞肺癌中已经广泛研究了耐药机制，但在ALK 驱动的间变大细胞淋巴瘤（ALCL）中，这些机制的了解甚少。在这里，我们确定了一种由肿瘤微环境支持的生存途径，该途径通过 C-C 基序趋化因子受体 7（CCR7）激活磷脂酰肌醇 3-激酶 γ（PI3K-γ）信号传导。我们发现，在对 ALK TKI 耐药的患者和 ALCL 细胞系中，PI3K 信号增加。PI3Kγ 的表达可预测 ALCL 患者对 ALK TKI 无反应。在 ALK 或 STAT3 抑制或降解期间，CCR7、PI3Kγ 和 PI3Kδ 的表达上调，并且组成性激活的 PI3Kγ 同工型与致癌性 ALK 协同作用，在小鼠中加速淋巴瘤的发生。在三维微流控芯片中，产生 CCR7 配体 CCL19/CCL21 的内皮细胞可保护 ALCL 细胞免受克唑替尼诱导的凋亡。PI3Kγ/δ 抑制剂 duvelisib 增强了克唑替尼对 ALCL 系和患者来源异种移植物的活性。此外，在接受克唑替尼治疗的小鼠中，CCR7 的基因缺失阻止了 ALCL 的中枢神经系统扩散和血管周围生长。因此，PI3Kγ 或 CCR7 信号阻断与 ALK TKI 治疗一起可降低 ALCL 中的原发性耐药性和持久性淋巴瘤细胞的存活。
