Yang Jingmei, Friedman Ran
Department of Chemistry and Biomedical Sciences, Linnaeus University, Kalmar, SE-39231, Sweden.
Biochem Biophys Rep. 2025 Jan 16;41:101894. doi: 10.1016/j.bbrep.2024.101894. eCollection 2025 Mar.
Acute myeloid leukaemia (AML) is a hard to treat blood cancer. Mutations in FLT3 are common among the genetic aberrations that characterise the cancer. Patients initially react to FLT3 inhibitors but drug resistance is a hinder to successful therapy. To better understand the mechanisms leading to drug resistance, we generated four AML cell lines resistant to the inhibitors gilteritinib or FF-10101, and explored their resistance mechanisms. We further tested whether the novel inhibitor Chen-9u could be used to limit cell growth. The results showed that each of the four resistant cell lines became resistant through a different mechanism. Resistant cells showed decreased FLT3 and increased NRAS pathway activity and reduced DNA synthesis due to decrease in CDK4 activity. Resistance mechanisms included resistance mutations in FLT3 (C695F and N701K), and a novel mutation in NRAS (G12C). In a fourth line, resistance might have developed through a MYCN mutation. Cell growth was inhibited by Chen-9u and resistant clones could not be obtained with this inhibitor. The results highlight opportunities and limitations. On the one hand, resistant cells were produced due to different mechanisms, showing the versatility of tumour cells. Furthermore, resistance developed to the most advanced inhibitors, one of which is covalent and the other non-covalent but highly specific. On the other hand, it is shown that DNA synthesis is reduced, which means that resistance has evolutionary consequences. Finally, the novel drug-resistant cell lines may serve as useful models for better understanding of the cellular events associated with inherent and acquired drug resistance.
急性髓系白血病（AML）是一种难以治疗的血癌。FLT3突变在该癌症特征性的基因畸变中很常见。患者最初对FLT3抑制剂有反应，但耐药性是成功治疗的一个障碍。为了更好地理解导致耐药性的机制，我们生成了四种对吉列替尼或FF - 10101抑制剂耐药的AML细胞系，并探索了它们的耐药机制。我们进一步测试了新型抑制剂Chen - 9u是否可用于限制细胞生长。结果表明，这四种耐药细胞系中的每一种都通过不同的机制产生耐药性。耐药细胞显示FLT3降低、NRAS通路活性增加以及由于CDK4活性降低导致DNA合成减少。耐药机制包括FLT3中的耐药突变（C695F和N701K）以及NRAS中的一种新型突变（G12C）。在第四种细胞系中，耐药性可能是通过MYCN突变产生的。Chen - 9u抑制了细胞生长，并且使用这种抑制剂无法获得耐药克隆。结果突出了机会和局限性。一方面，由于不同机制产生了耐药细胞，显示出肿瘤细胞的多样性。此外，对最先进的抑制剂产生了耐药性，其中一种是共价的，另一种是非共价但高度特异性的。另一方面，结果表明DNA合成减少，这意味着耐药性具有进化后果。最后，新型耐药细胞系可能作为有用的模型，用于更好地理解与固有和获得性耐药相关的细胞事件。
