Comprehensive biomarker and genomic analysis identifies p53 status as the major determinant of response to MDM2 inhibitors in chronic lymphocytic leukemia
Comprehensive biomarker and genomic analysis identifies p53 status as the major determinant of response to MDM2 inhibitors in chronic lymphocytic leukemia
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DOI：
10.1182/blood-2007-09-112698
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发表时间：
2008-02-01
期刊：
影响因子：
20.3
通讯作者：
Malek, Sami N.
中科院分区：
文献类型：
--
作者：
Saddler, Chris;Ouillette, Peter;Malek, Sami N.
慢性淋巴细胞白血病（CLL）是西方世界最常见的白血病，并且仍然无法用常规疗法治愈。复发或耐药CLL患者的寿命显著缩短。MDM2抑制剂已被开发出来，可能在治疗CLL方面具有重大潜力。这些化合物的临床开发将有助于通过分子预测活性的知识。为了了解CLL对MDM2抑制剂治疗的敏感性或耐药性的决定因素，我们全面分析了一个大型CLL患者来源的样本队列对MDM2抑制的反应，并将这些反应与临床重要的生物标志物相关联。此外，我们采用高密度单核苷酸多态性（SNP）阵列分析全基因组拷贝数和等位基因状态的变化，包括p53。这些研究的结果最终证明，p53状态是CLL对MDM2抑制剂反应的主要决定因素。p53调节级联反应中的其他缺陷在该白血病中似乎不起作用。此外，我们确定了一个新的CLL患者亚组，早期进展性疾病，似乎特别敏感的MDM2抑制剂治疗。这些数据为靶点特异性和预测活性提供了明确的证据，并为继续使用这类潜在重要的化合物治疗CLL提供了理论基础。
Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world and remains incurable with conventional therapies. Patients with relapsed or resistant CLL have a significantly shortened lifespan. MDM2 inhibitors have been developed and may have significant potential in the treatment of CLL. Clinical development of these compounds would be aided through knowledge of molecular predictors of activity. To understand determinants of sensitivity or resistance to MDM2 inhibitor therapy in CLL, we comprehensively analyzed a large cohort of CLL patient-derived samples for response to MDM2 inhibition and correlated these responses with clinically important biomarkers. Furthermore, we employed high-density single nucleotide polymorphism (SNP) arrays to analyze genomewide changes of copy number and allele status, including that of p53. The results of these studies conclusively demonstrate that p53 status is the major determinant of response to MDM2 inhibitors in CLL. Additional defects in the p53 regulatory cascade do not appear operational in this leukemia. Further, we identify a novel subgroup of patients with CLL with early progressive disease that appears particularly sensitive to MDM2 inhibitor treatment. These data provide definitive evidence for target-specific and predictive activity and a rationale to proceed with this potentially important class of compounds in the treatment of CLL.