The Philadelphia chromosome negative myeloproliferative neoplasms, including polycythemia vera, essential thrombocytosis, and myelofibrosis, are driven by hyper activation of the JAK2 tyrosine kinase, the result of mutations in three MPN driving genes: JAK2, MPL, and CALR. While the anti-inflammatory effects of JAK2 inhibitors can provide improved quality of life for many MPN patients, the upfront and persistent survival of disease-driving cells in MPN patients undergoing JAK2 inhibitor therapy thwarts potential for remission. Early studies indicated JAK2 inhibitor therapy induces heterodimeric complex formation of JAK2 with other JAK family members leading to sustained JAK2-dependent signaling. Recent work has described novel cell intrinsic details as well as cell extrinsic mechanisms that may contribute to why JAK2 inhibition may be ineffective at targeting MPN driving cells. Diverse experimental strategies aimed at uncovering mechanistic details that contribute to JAK2 inhibitor persistence have each highlighted the role of MEK/ERK activation. These approaches include, among others, phosphoproteomic analyses of JAK2 signaling as well as detailed assessment of JAK2 inhibition in mouse models of MPN. In this focused review, we highlight these and other studies that collectively suggest targeting MEK/ERK in combination with JAK2 inhibition has the potential to improve the efficacy of JAK2 inhibitors in MPN patients. As MPN patients patiently wait for improved therapies, such studies should further strengthen optimism that pre-clinical research is continuing to uncover mechanistic insights regarding the ineffectiveness of JAK2 inhibitors, which may lead to development of improved therapeutic strategies.
费城染色体阴性骨髓增殖性肿瘤，包括真性红细胞增多症、原发性血小板增多症和骨髓纤维化，主要由JAK2酪氨酸激酶的过度活化驱动，该活化源于JAK2、MPL和CALR这三种MPN驱动基因的突变。尽管JAK2抑制剂的抗炎作用可改善许多MPN患者的生活质量，但在接受JAK2抑制剂治疗的患者中，疾病驱动细胞的早期持续存活阻碍了病情缓解的可能。早期研究表明，JAK2抑制剂治疗会诱导JAK2与其他JAK家族成员形成异二聚体复合物，从而导致持续的JAK2依赖性信号传导。近期研究揭示了新的细胞内在机制与外在机制，这些机制可能解释为何JAK2抑制剂对靶向MPN驱动细胞效果有限。多种旨在揭示JAK2抑制剂耐药机制的实验策略均强调了MEK/ERK通路激活的关键作用，其中包括JAK2信号通路的磷酸化蛋白质组学分析，以及在MPN小鼠模型中进行的JAK2抑制效应精细评估。本篇专题综述重点讨论这些研究及其他相关工作，它们共同表明联合靶向MEK/ERK与JAK2抑制有望提升JAK2抑制剂对MPN患者的疗效。在MPN患者殷切期待更好疗法的同时，此类研究应进一步增强我们的信心：临床前研究将持续揭示JAK2抑制剂失效的内在机制，从而推动改良治疗策略的发展。
JAK2 inhibitor persistence in MPN: uncovering a central role of ERK activation
肿瘤(癌症)患者之家