Kawasoe Kazunori, Watanabe Tatsuro, Yoshida-Sakai Nao, Yamamoto Yuta, Kurahashi Yuki, Kidoguchi Keisuke, Ureshino Hiroshi, Kamachi Kazuharu, Fukuda-Kurahashi Yuki, Kimura Shinya
Department of Drug Discovery and Biomedical Sciences, Faculty of Medicine, Saga University, Saga 849-8501, Japan.
Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga 849-8501, Japan.
Cancers (Basel). 2023 Oct 21;15(20):5089. doi: 10.3390/cancers15205089.
The recent evolution of molecular targeted therapy has improved clinical outcomes in several human malignancies. The translocation of anaplastic lymphoma kinase (ALK) was originally identified in anaplastic large-cell lymphoma (ALCL) and subsequently in non-small cell lung carcinoma (NSCLC). Since fusion gene products act as a driver of carcinogenesis in both ALCL and NSCLC, several ALK tyrosine kinase inhibitors (TKIs) have been developed. Crizotinib and alectinib are first- and second-generation ALK TKIs, respectively, approved for the treatment of ALK-positive ALCL (ALK ALCL) and ALK NSCLC. Although most ALK NSCLC patients respond to crizotinib and alectinib, they generally relapse after several years of treatment. We previously found that DNA-demethylating agents enhanced the efficacy of ABL TKIs in chronic myeloid leukemia cells. Moreover, aberrant DNA methylation has also been observed in ALCL cells. Thus, to improve the clinical outcomes of ALK ALCL therapy, we investigated the synergistic efficacy of the combination of alectinib and the DNA-demethylating agent azacytidine, decitabine, or OR-2100 (an orally bioavailable decitabine derivative). As expected, the combination of alectinib and DNA-demethylating agents synergistically suppressed ALK ALCL cell proliferation, concomitant with DNA hypomethylation and a reduction in STAT3 (a downstream target of ALK fusion proteins) phosphorylation. The combination of alectinib and OR-2100 markedly altered gene expression in ALCL cells, including that of genes implicated in apoptotic signaling, which possibly contributed to the synergistic anti-ALCL effects of this drug combination. Therefore, alectinib and OR-2100 combination therapy has the potential to improve the outcomes of patients with ALK ALCL.
分子靶向治疗的最新进展改善了多种人类恶性肿瘤的临床疗效。间变性淋巴瘤激酶（ALK）的易位最初在间变性大细胞淋巴瘤（ALCL）中被发现，随后在非小细胞肺癌（NSCLC）中也被发现。由于融合基因产物在ALCL和NSCLC中均作为致癌驱动因素，因此已开发出几种ALK酪氨酸激酶抑制剂（TKIs）。克唑替尼和阿来替尼分别是第一代和第二代ALK TKIs，被批准用于治疗ALK阳性的ALCL（ALK-ALCL）和ALK NSCLC。尽管大多数ALK NSCLC患者对克唑替尼和阿来替尼有反应，但他们通常在治疗几年后复发。我们之前发现DNA去甲基化剂可增强ABL TKIs在慢性髓性白血病细胞中的疗效。此外，在ALCL细胞中也观察到了异常的DNA甲基化。因此，为了改善ALK-ALCL治疗的临床疗效，我们研究了阿来替尼与DNA去甲基化剂阿扎胞苷、地西他滨或OR-2100（一种口服生物可利用的地西他滨衍生物）联合使用的协同疗效。正如预期的那样，阿来替尼与DNA去甲基化剂联合使用可协同抑制ALK-ALCL细胞增殖，同时伴有DNA低甲基化和STAT3（ALK融合蛋白的下游靶点）磷酸化的减少。阿来替尼与OR-2100联合使用显著改变了ALCL细胞中的基因表达，包括与凋亡信号相关的基因表达，这可能有助于这种药物组合产生协同抗ALCL效应。因此，阿来替尼与OR-2100联合治疗有可能改善ALK-ALCL患者的治疗效果。
