Supplementary file 1_Acute myeloid leukemia drug resistance: targetable nodes and the clinical trajectory of small-molecule inhibitors.docx

Acute myeloid leukemia (AML) is paradigmatic for therapeutic resistance driven by genetic heterogeneity, epigenetic plasticity and microenvironmental protection. Over the past decade, six targeted or pathway-directed small molecules—midostaurin, gilteritinib, quizartinib, ivosidenib, enasidenib, venetoclax and glasdegib—have changed frontline and relapsed/refractory (R/R) practice in genomically defined subgroups or in patients unfit for intensive chemotherapy. Yet primary refractoriness and early relapse remain common, frequently via adaptive rewiring of apoptotic dependencies, clonal evolution and differentiation resistance. Here we integrate mechanistic insights with clinical evidence to: (i) map resistance biology onto targetable nodes (apoptosis control; signalling kinases; chromatin/lineage programmes; RNA splicing; DNA-damage response; nuclear export; niche adhesion and innate immune evasion); (ii) summarise the clinical trajectory and current limits of approved and emerging small molecules (including menin and LSD1 inhibitors); (iii) propose rules for rational doublets and triplets that are biologically orthogonal yet clinically tolerable; (iv) outline a regulatory timeline for key AML small molecules; and (v) prioritise where drug development should go next, including next-generation BH3 toolkits, clonal-pressure-aware designs, minimal residual disease (MRD)–adapted trials and therapy guided by dynamic functional profiling. The review closes with cross-platform challenges—myelosuppression, infectious risk, resistance monitoring and trial design—and a pragmatic framework for moving beyond incrementalism toward durable control and cure.

急性髓系白血病（Acute myeloid leukemia, AML）是由遗传异质性、表观遗传可塑性及微环境保护作用驱动的治疗耐药的典型范例。过去十年间，米哚妥林（midostaurin）、吉瑞替尼（gilteritinib）、奎扎替尼（quizartinib）、艾伏尼布（ivosidenib）、恩西地平（enasidenib）、维奈克拉（venetoclax）与格拉吉布（glasdegib）这6款靶向或通路导向小分子药物，已改变了基因组定义亚组患者或不适合强化化疗患者的一线及复发/难治性（R/R）临床诊疗实践。然而原发性耐药与早期复发仍较为常见，其发生常与凋亡依赖通路的适应性重编程、克隆进化及分化耐药相关。本研究整合机制认知与临床证据，旨在：(i) 将耐药生物学特征映射至可靶向节点（包括凋亡调控、信号激酶、染色质/细胞谱系程序、RNA剪接、DNA损伤应答、核输出、龛黏附及先天免疫逃逸）；(ii) 总结已获批及在研小分子药物（包括膜内蛋白（menin）抑制剂与赖氨酸特异性去甲基化酶1（LSD1）抑制剂）的临床诊疗历程与当前局限；(iii) 提出兼具生物学正交性与临床可耐受性的合理双药、三药联合方案的制定原则；(iv) 梳理关键急性髓系白血病小分子药物的监管时间线；(v) 明确药物开发的优先方向，包括新一代BH3结构域工具、考虑克隆压力的试验设计、适配微小残留病（MRD）的临床试验，以及基于动态功能谱的治疗方案。本综述最后探讨了跨平台挑战——包括骨髓抑制、感染风险、耐药监测与试验设计，并提出了一套务实框架，以推动研究超越渐进式改进，迈向持久的疾病控制与治愈。