German Cancer Consortium (DKTK), Heidelberg, Germany; Molecular & Translational Radiation Oncology, Heidelberg Ion Therapy Center (HIT), Germany.
German Cancer Consortium (DKTK), Heidelberg, Germany; Molecular & Translational Radiation Oncology, Heidelberg Ion Therapy Center (HIT), Germany; Department of Clinical Pathology, Suez Canal University, Ismailia, Egypt.
Radiother Oncol. 2015 Feb;114(2):173-81. doi: 10.1016/j.radonc.2014.12.009. Epub 2015 Jan 12.
Non-small cell lung cancer (NSCLC) patients with chromosomal rearrangements of the anaplastic lymphoma kinase gene (ALK) are sensitive to the tyrosine kinase inhibitor crizotinib. We aimed to investigate the effects of combined radiotherapy and crizotinib in ALK-positive vs. wild type NSCLC models.
Clonogenic survival, proliferation and apoptosis of cells exposed to crizotinib and radiotherapy (photon and carbon ions) were evaluated in ALK mutation positive (ALK+; H3122) and negative (ALK-; A549 and LLC) NSCLC lines. The syngeneic mouse (LLC) and human (H3122) xenograft tumor models were further studied in vivo. Tumor growth kinetics, microvascular density (MVD), perfusion and proliferation were assessed.
Crizotinib exerted potent and selective anti-proliferative and pro-apoptotic effects in ALK+ H3122 cells which were augmented by radiotherapy. The synergistic effect of this combination in ALK+ NSCLC was confirmed by isobologram analysis. Crizotinib also sensitized H3122 cells to particle therapy with carbon ions. In H3122 xenografts, dual combination was most effective in reducing tumor proliferation, MVD and perfusion. In contrast, in the LLC model, crizotinib led only to a transient tumor growth inhibition and combined treatment was inferior to radiotherapy alone.
Crizotinib elicits beneficial effects in combination with radiotherapy only in ALK-positive NSCLC.
具有间变性淋巴瘤激酶基因（ALK）染色体重排的非小细胞肺癌（NSCLC）患者对酪氨酸激酶抑制剂克唑替尼敏感。我们旨在研究 ALK 阳性与野生型 NSCLC 模型中联合放疗和克唑替尼的效果。
在 ALK 突变阳性（ALK+；H3122）和阴性（ALK-；A549 和 LLC）NSCLC 细胞系中，评估了暴露于克唑替尼和放疗（光子和碳离子）后细胞的集落存活、增殖和凋亡。进一步在体内研究了同源小鼠（LLC）和人源（H3122）异种移植肿瘤模型。评估了肿瘤生长动力学、微血管密度（MVD）、灌注和增殖。
克唑替尼对 ALK+ H3122 细胞表现出强大且选择性的抗增殖和促凋亡作用，而放疗则增强了这种作用。通过等辐射效应分析，证实了这种联合在 ALK+ NSCLC 中的协同作用。克唑替尼还使 H3122 细胞对碳离子粒子疗法敏感。在 H3122 异种移植瘤中，双重联合在降低肿瘤增殖、MVD 和灌注方面最有效。相比之下，在 LLC 模型中，克唑替尼仅导致肿瘤生长短暂抑制，联合治疗不如单独放疗有效。
克唑替尼与放疗联合仅在 ALK 阳性 NSCLC 中产生有益效果。
