Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University Knight Cancer Institute, Portland, OR.
Department of Medicine, Division of Hematology, Cancer Institute, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA.
Nat Cancer. 2020 Aug;1(8):826-839. doi: 10.1038/s43018-020-0103-x. Epub 2020 Aug 18.
Deregulation of the gene family plays an important role in the pathogenesis of acute myeloid leukemia (AML). The BCL2 inhibitor, venetoclax, has received FDA approval for the treatment of AML. However, upfront and acquired drug resistance ensues due, in part, to the clinical and genetic heterogeneity of AML, highlighting the importance of identifying biomarkers to stratify patients onto the most effective therapies. By integrating clinical characteristics, exome and RNA sequencing, and inhibitor data from primary AML patient samples, we determined that myelomonocytic leukemia, upregulation of and , as well as mutations of and conferred resistance to venetoclax and multiple venetoclax combinations. Venetoclax in combination with an MCL1 inhibitor AZD5991 induced synthetic lethality and circumvented venetoclax resistance.
基因家族的失调在急性髓细胞白血病（AML）的发病机制中起着重要作用。BCL2 抑制剂 venetoclax 已获得 FDA 批准用于治疗 AML。然而，由于 AML 的临床和遗传异质性，导致耐药性的出现，这凸显了确定生物标志物以将患者分层到最有效的治疗方法的重要性。通过整合原发性 AML 患者样本的临床特征、外显子组和 RNA 测序以及抑制剂数据，我们确定了髓单核细胞白血病、和的上调以及和的突变赋予了 venetoclax 和多种 venetoclax 组合的耐药性。venetoclax 与 MCL1 抑制剂 AZD5991 联合使用可诱导合成致死并规避 venetoclax 耐药性。
