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). SinceALKfusion 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已改善多种人类恶性肿瘤的临床预后。间变性淋巴瘤激酶（ALK）易位最初在间变性大细胞淋巴瘤（ALCL）中发现，随后在非小细胞肺癌（NSCLC）中亦被确认。由于ALK融合基因产物在ALCL和NSCLC中均作为致癌驱动因子，多种ALK酪氨酸激酶抑制剂（TKIs）得以研发。克唑替尼和阿来替尼分别作为第一代和第二代ALK TKI，已获批用于治疗ALK阳性ALCL（ALK+ALCL）与ALK阳性NSCLC。尽管多数ALK阳性NSCLC患者对克唑替尼和阿来替尼产生应答，但通常在治疗数年后出现复发。我们既往研究发现，DNA去甲基化药物能增强ABL TKI在慢性髓系白血病细胞中的疗效。此外，ALCL细胞中也观察到异常的DNA甲基化现象。因此，为改善ALK+ALCL治疗的临床预后，我们研究了阿来替尼与DNA去甲基化药物（阿扎胞苷、地西他滨或口服生物可利用的地西他滨衍生物OR-2100）联合应用的协同疗效。如预期所示，阿来替尼与DNA去甲基化药物的联合应用能协同抑制ALK+ALCL细胞增殖，同时伴随DNA低甲基化及STAT3（ALK融合蛋白下游靶点）磷酸化水平降低。阿来替尼与OR-2100的联用显著改变了ALCL细胞的基因表达谱，包括涉及凋亡信号通路的基因，这可能是该药物组合产生协同抗ALCL效应的机制之一。因此，阿来替尼与OR-2100的联合治疗方案具有改善ALK+ALCL患者预后的潜力。
肿瘤(癌症)患者之家