Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
J Exp Med. 2012 Feb 13;209(2):259-73. doi: 10.1084/jem.20111694. Epub 2012 Jan 23.
Enzymatic inhibitors of Janus kinase 2 (JAK2) are in clinical development for the treatment of myeloproliferative neoplasms (MPNs), B cell acute lymphoblastic leukemia (B-ALL) with rearrangements of the cytokine receptor subunit cytokine receptor-like factor 2 (CRLF2), and other tumors with constitutive JAK2 signaling. In this study, we identify G935R, Y931C, and E864K mutations within the JAK2 kinase domain that confer resistance across a panel of JAK inhibitors, whether present in cis with JAK2 V617F (observed in MPNs) or JAK2 R683G (observed in B-ALL). G935R, Y931C, and E864K do not reduce the sensitivity of JAK2-dependent cells to inhibitors of heat shock protein 90 (HSP90), which promote the degradation of both wild-type and mutant JAK2. HSP90 inhibitors were 100-1,000-fold more potent against CRLF2-rearranged B-ALL cells, which correlated with JAK2 degradation and more extensive blockade of JAK2/STAT5, MAP kinase, and AKT signaling. In addition, the HSP90 inhibitor AUY922 prolonged survival of mice xenografted with primary human CRLF2-rearranged B-ALL further than an enzymatic JAK2 inhibitor. Thus, HSP90 is a promising therapeutic target in JAK2-driven cancers, including those with genetic resistance to JAK enzymatic inhibitors.
Janus 激酶 2（JAK2）的酶抑制剂正在开发中，用于治疗骨髓增殖性肿瘤（MPN）、伴有细胞因子受体亚基细胞因子受体样因子 2（CRLF2）重排的 B 细胞急性淋巴细胞白血病（B-ALL），以及其他具有组成性 JAK2 信号的肿瘤。在这项研究中，我们在 JAK2 激酶结构域中鉴定出 G935R、Y931C 和 E864K 突变，这些突变赋予了对一系列 JAK 抑制剂的耐药性，无论这些突变是与 JAK2 V617F（在 MPN 中观察到）还是 JAK2 R683G（在 B-ALL 中观察到）共位存在。G935R、Y931C 和 E864K 并没有降低 JAK2 依赖性细胞对热休克蛋白 90（HSP90）抑制剂的敏感性，HSP90 抑制剂促进野生型和突变型 JAK2 的降解。HSP90 抑制剂对 CRLF2 重排的 B-ALL 细胞的效力高出 100-1000 倍，这与 JAK2 降解和更广泛的 JAK2/STAT5、MAP 激酶和 AKT 信号阻断相关。此外，HSP90 抑制剂 AUY922 延长了异种移植原发性人 CRLF2 重排 B-ALL 的小鼠的存活时间，比酶促 JAK2 抑制剂更长。因此，HSP90 是 JAK2 驱动的癌症的一个有前途的治疗靶点，包括对 JAK 酶抑制剂具有遗传耐药性的癌症。
