Van Nguyen Tai, Angeli Eurydice, Hamdan Diaddin, El Bouchtaoui Morad, Bui Oanh T, Azibani Feriel, Shen Rong, Lu He, Do Kien Hung, Janin Anne, Van Le Quang, Bousquet Guilhem
Université de Paris, INSERM, MASCOT, 75006, Paris, France.
Vietnam National Cancer Hospital - K Hospital, Hanoi, Vietnam.
Exp Hematol Oncol. 2025 Apr 19;14(1):59. doi: 10.1186/s40164-025-00640-9.
Anti-angiogenic tyrosine kinase inhibitors (TKIs) have become major drugs for the treatment of various cancer types, but with an overall high incidence of severe toxicities, particularly haematological toxicities including severe anemia.
We treated C57BL6 mice continuously by gavage for 14 days with either sunitinib, pazopanib, or axitinib. In this study, we set out to decipher the pathophysiological mechanisms of anti-angiogenic TKI haematological toxicity.
We demonstrated that anti-angiogenic TKIs induced a broad range of toxic effects on normal tissues through a cytotoxic effect on normal endothelial cells. Haematological toxicities were particulary marked with sunitinib. Sunitinib-induced hypoxia through the destruction of normal vessels in the bone marrow mainly affected erythrocyte and myeloid lineages, and this was associated with a blockage in erythrocyte maturation. Althought sunitinib-induced anemia was associated with an adaptative response to systemic hypoxia, we demonstrated that erythropoietin (EPO) concentrations in the total bone marrow of sunitinib-treated mice were significantly lower than in untreated mice. This is coherent with the destruction of microvessels in the bone marrow under sunitinib treatment, preventing circulating EPO from reaching the bone marrow at relevant concentrations. However, we demonstrated an additional effect specific to sunitinib that induced autophagy flux inhibition in erythroid progenitors, with a blockage of erythrocyte maturation, leading to more severe anemia.
We deciphered the pathophysiology of anti-angiogenic TKI-induced anemia, which we observed to be mainly linked to a direct effect on normal bone-marrow vessels and to autophagy flux inhibition in erythroid progenitors under sunitinib.
抗血管生成酪氨酸激酶抑制剂（TKIs）已成为治疗多种癌症类型的主要药物，但总体严重毒性发生率较高，尤其是包括严重贫血在内的血液学毒性。
我们用舒尼替尼、帕唑帕尼或阿昔替尼对C57BL6小鼠连续灌胃14天。在本研究中，我们着手解读抗血管生成TKI血液学毒性的病理生理机制。
我们证明，抗血管生成TKIs通过对正常内皮细胞的细胞毒性作用，对正常组织产生广泛的毒性影响。血液学毒性在舒尼替尼治疗时尤为明显。舒尼替尼通过破坏骨髓中的正常血管诱导缺氧，主要影响红细胞和髓系谱系，这与红细胞成熟受阻有关。虽然舒尼替尼诱导的贫血与对全身缺氧的适应性反应有关，但我们证明，舒尼替尼治疗小鼠的全骨髓中促红细胞生成素（EPO）浓度显著低于未治疗小鼠。这与舒尼替尼治疗下骨髓微血管的破坏相一致，阻止循环中的EPO以相关浓度到达骨髓。然而，我们证明了舒尼替尼特有的另一种效应，即诱导红系祖细胞自噬流抑制，导致红细胞成熟受阻，从而导致更严重的贫血。
我们解读了抗血管生成TKI诱导贫血的病理生理学，我们观察到这主要与对正常骨髓血管的直接作用以及舒尼替尼作用下红系祖细胞自噬流抑制有关。
