De Novellis Danilo, Cacace Fabiana, Caprioli Valeria, Wierda William G, Mahadeo Kris M, Tambaro Francesco Paolo
Hematology and Transplant Center, University "Hospital San Giovanni di Dio e Ruggi D'Aragona", 84131 Salerno, Italy.
Unità Operativa di Trapianto di Cellule Staminali Ematopoietiche e Terapie Cellulari, Azienda Ospedaliera di Rilievo Nazionale Santobono-Pausilipon, 80123 Napoli, Italy.
Pharmaceutics. 2021 Dec 20;13(12):2201. doi: 10.3390/pharmaceutics13122201.
Tyrosine kinases are proteins involved in physiological cell functions including proliferation, differentiation, and survival. However, the dysregulation of tyrosine kinase pathways occurs in malignancy, including hematological leukemias such as chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL). Particularly, the fusion oncoprotein BCR-ABL1 in CML and the B-cell receptor (BCR) signaling pathway in CLL are critical for leukemogenesis. Therapeutic management of these two hematological conditions was fundamentally changed in recent years, making the role of conventional chemotherapy nearly obsolete. The first, second, and third generation inhibitors (imatinib, dasatinib, nilotinib, bosutinib, and ponatinib) of BCR-ABL1 and the allosteric inhibitor asciminib showed deep genetic and molecular remission rates in CML, leading to the evaluation of treatment discontinuation in prospective trials. The irreversible BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib, tirabrutinib, and spebrutinib) covalently bind to the C481 amino acid of BTK. The reversible BTK inhibitor pirtobrutinib has a different binding site, overcoming resistance associated with mutations at C481. The PI3K inhibitors (idelalisib and duvelisib) are also effective in CLL but are currently less used because of their toxicity profiles. These tyrosine kinase inhibitors are well-tolerated, do have some associated in-class side effects that are manageable, and have remarkably improved outcomes for patients with hematologic malignancies.
酪氨酸激酶是参与细胞生理功能的蛋白质，包括增殖、分化和存活。然而，酪氨酸激酶途径的失调发生在恶性肿瘤中，包括血液系统白血病，如慢性髓性白血病（CML）和慢性淋巴细胞白血病（CLL）。特别是，CML中的融合癌蛋白BCR-ABL1和CLL中的B细胞受体（BCR）信号通路对白血病发生至关重要。近年来，这两种血液系统疾病的治疗管理发生了根本性变化，使得传统化疗的作用几乎过时。BCR-ABL1的第一代、第二代和第三代抑制剂（伊马替尼、达沙替尼、尼洛替尼、博舒替尼和波纳替尼）以及变构抑制剂阿塞西尼布在CML中显示出深度基因和分子缓解率，从而在前瞻性试验中对停药进行评估。不可逆的BTK抑制剂（依鲁替尼、阿卡替尼、泽布替尼、替拉鲁替尼和斯布替尼）与BTK的C481氨基酸共价结合。可逆的BTK抑制剂 pirtobrutinib具有不同的结合位点，可以克服与C481突变相关的耐药性。PI3K抑制剂（艾代拉里斯和度维利西布）在CLL中也有效，但由于其毒性特征，目前较少使用。这些酪氨酸激酶抑制剂耐受性良好，确实存在一些可管理的同类相关副作用，并且显著改善了血液系统恶性肿瘤患者的治疗效果。
