Marr Alexander R, Halpin Madeline, Corbin Dominique L, Asemelash Yerdanos, Sher Steven, Gordon Britten K, Whipp Ethan C, Mitchell Shaneice, Harrington Bonnie K, Orwick Shelley, Benrashid Samon, Goettl Virginia M, Yildiz Vedat, Mitchell Andrew D, Cahn Olivia, Mims Alice S, Larkin Karilyn T M, Long Meixao, Blachly James, Woyach Jennifer A, Lapalombella Rosa, Grieselhuber Nicole R
Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
Department of Pathology, Stanford University, Stanford, CA, USA.
Exp Hematol Oncol. 2024 Mar 4;13(1):27. doi: 10.1186/s40164-024-00483-w.
Acute myeloid leukemia (AML) is a highly aggressive hematologic cancer with poor survival across a broad range of molecular subtypes. Development of efficacious and well-tolerable therapies encompassing the range of mutations that can arise in AML remains an unmet need. The bromo- and extra-terminal domain (BET) family of proteins represents an attractive therapeutic target in AML due to their crucial roles in many cellular functions, regardless of any specific mutation. Many BET inhibitors (BETi) are currently in pre-clinical and early clinical development, but acquisition of resistance continues to remain an obstacle for the drug class. Novel methods to circumvent this development of resistance could be instrumental for the future use of BET inhibitors in AML, both as monotherapy and in combination. To date, many investigations into possible drug combinations of BETi with CDK inhibitors have focused on CDK9, which has a known physical and functional interaction with the BET protein BRD4. Therefore, we wished to investigate possible synergy and additive effects between inhibitors of these targets in AML. Here, we describe combination therapy with the multi-CDK inhibitor dinaciclib and the BETi PLX51107 in pre-clinical models of AML. Dinaciclib and PLX51107 demonstrate additive effects in AML cell lines, primary AML samples, and in vivo. Further, we demonstrate novel activity of dinaciclib through inhibition of the canonical/β-catenin dependent Wnt signaling pathway, a known resistance mechanism to BETi in AML. We show dinaciclib inhibits Wnt signaling at multiple levels, including downregulation of β-catenin, the Wnt co-receptor LRP6, as well as many Wnt pathway components and targets. Moreover, dinaciclib sensitivity remains unaffected in a setting of BET resistance, demonstrating similar inhibitory effects on Wnt signaling when compared to BET-sensitive cells. Ultimately, our results demonstrate rationale for combination CDKi and BETi in AML. In addition, our novel finding of Wnt signaling inhibition could have potential implications in other cancers where Wnt signaling is dysregulated and demonstrates one possible approach to circumvent development of BET resistance in AML.
急性髓系白血病（AML）是一种侵袭性很强的血液系统癌症，在广泛的分子亚型中生存率都很低。开发涵盖AML中可能出现的各种突变且疗效显著、耐受性良好的疗法仍是未满足的需求。含溴结构域和额外末端结构域（BET）蛋白家族因其在许多细胞功能中发挥关键作用，成为AML中一个有吸引力的治疗靶点，无论是否存在特定突变。目前许多BET抑制剂（BETi）正处于临床前和早期临床开发阶段，但获得性耐药仍然是该类药物面临的障碍。规避这种耐药性发展的新方法可能有助于未来BET抑制剂在AML中作为单一疗法或联合疗法的应用。迄今为止，许多关于BETi与CDK抑制剂联合用药可能性的研究都集中在CDK9上，它与BET蛋白BRD4存在已知的物理和功能相互作用。因此，我们希望研究这些靶点的抑制剂在AML中可能产生的协同和相加作用。在此，我们描述了在AML临床前模型中多靶点CDK抑制剂地西他滨和BETi PLX51107的联合治疗。地西他滨和PLX51107在AML细胞系、原发性AML样本以及体内均表现出相加作用。此外，我们通过抑制经典/β-连环蛋白依赖性Wnt信号通路证明了地西他滨的新活性，这是AML中已知的对BETi的耐药机制。我们发现地西他滨在多个水平上抑制Wnt信号，包括下调β-连环蛋白、Wnt共受体LRP6以及许多Wnt信号通路成分和靶点。此外，在BET耐药的情况下，地西他滨的敏感性不受影响，与BET敏感细胞相比，对Wnt信号表现出相似的抑制作用。最终，我们的结果证明了在AML中联合使用CDKi和BETi的合理性。此外，我们对Wnt信号抑制的新发现可能对其他Wnt信号失调的癌症有潜在影响，并展示了一种在AML中规避BET耐药性发展的可能方法。
