Lagonik Elias, Page Elyse C, Bruning John B, Eadie Laura N, Heatley Susan L, Greenwood Matthew, Fong Chun Y, Moore Andrew S, Yeung David T, Hughes Timothy P, White Deborah L
Blood Cancer Program, Precision Cancer Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia.
School of Biological Sciences, Faculty of Sciences, Engineering and Technology, The University of Adelaide, Adelaide, SA, Australia.
Blood Neoplasia. 2025 Apr 25;2(3):100109. doi: 10.1016/j.bneo.2025.100109. eCollection 2025 Aug.
rearranged () acute lymphoblastic leukemia (ALL) is a subtype of high-risk Philadelphia chromosome-like ALL. Patients with ALL are treated with high-dose multiagent chemotherapy, and the addition of tyrosine kinase inhibitors to their treatment regimen is currently being explored. We have previously demonstrated the in vitro sensitivity of cells harboring the :: fusion to asciminib, the first inhibitor that specifically targets the Abl myristate pocket (STAMP). In this study, we extended these in vitro findings to demonstrate similar sensitivity to the second-generation STAMP inhibitor, TERN-701, using :: ALL cells. In addition, using truncated :: isoforms, we identified that exon 3 of Abl2 (encoded by ) is essential for the efficacy of both STAMP inhibitors. In an in silico model, we further demonstrated that different myristate pocket residues impact the effective binding of asciminib to Abl2 compared to Abl. Importantly, this suggests that, in the clinical setting, different asciminib binding site mutations may be anticipated with STAMP treatment for ALL. Finally, we demonstrated the efficacy of both STAMP inhibitors against cells from patients with :: and asciminib as a novel treatment for :: disease in a preclinical in vivo study.
重排型急性淋巴细胞白血病（ALL）是高危费城染色体样ALL的一种亚型。ALL患者接受大剂量多药化疗，目前正在探索在其治疗方案中添加酪氨酸激酶抑制剂。我们之前已经证明，携带::融合的细胞对阿西替尼（asciminib）具有体外敏感性，阿西替尼是第一种特异性靶向Abl肉豆蔻酰口袋（STAMP）的抑制剂。在本研究中，我们将这些体外研究结果进行拓展，使用:: ALL细胞证明其对第二代STAMP抑制剂TERN-701具有相似的敏感性。此外，通过使用截短的::异构体，我们确定Abl2的外显子3（由编码）对于两种STAMP抑制剂的疗效至关重要。在计算机模型中，我们进一步证明，与Abl相比，不同的肉豆蔻酰口袋残基会影响阿西替尼与Abl2的有效结合。重要的是，这表明在临床环境中，对于:: ALL的STAMP治疗可能会预期出现不同的阿西替尼结合位点突变。最后，在一项临床前体内研究中，我们证明了两种STAMP抑制剂对::患者来源的细胞均有效，且阿西替尼可作为::疾病的一种新型治疗方法。
