Abivertinib inhibits megakaryocyte differentiation and platelet biogenesis
Jiansong Huang1,2(), Xin Huang1,2, Yang Li3, Xia Li1,2, Jinghan Wang1,2, Fenglin Li1,2, Xiao Yan4, Huanping Wang1,2, Yungui Wang1,2, Xiangjie Lin1,2, Jifang Tu1,2, Daqiang He5, Wenle Ye1,2, Min Yang1,2, Jie Jin1,6()
1. Department of Hematology, Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China 2. Institute of Hematology, Zhejiang University School of Medicine, Hangzhou 310003, China 3. Department of Obstetrics, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China 4. Department of Hematology, Qingdao Municipal Hospital, Qingdao 266000, China 5. Department of Laboratory Medicine, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China 6. Cancer Center, Zhejiang University, Hangzhou 310058, China
Abivertinib, a third-generation tyrosine kinase inhibitor, is originally designed to target epidermal growth factor receptor (EGFR)-activating mutations. Previous studies have shown that abivertinib has promising antitumor activity and a well-tolerated safety profile in patients with non-small-cell lung cancer. However, abivertinib also exhibited high inhibitory activity against Bruton’s tyrosine kinase and Janus kinase 3. Given that these kinases play some roles in the progression of megakaryopoiesis, we speculate that abivertinib can affect megakaryocyte (MK) differentiation and platelet biogenesis. We treated cord blood CD34+ hematopoietic stem cells, Meg-01 cells, and C57BL/6 mice with abivertinib and observed megakaryopoiesis to determine the biological effect of abivertinib on MK differentiation and platelet biogenesis. Our in vitro results showed that abivertinib impaired the CFU-MK formation, proliferation of CD34+ HSC-derived MK progenitor cells, and differentiation and functions of MKs and inhibited Meg-01-derived MK differentiation. These results suggested that megakaryopoiesis was inhibited by abivertinib. We also demonstrated in vivo that abivertinib decreased the number of MKs in bone marrow and platelet counts in mice, which suggested that thrombopoiesis was also inhibited. Thus, these preclinical data collectively suggested that abivertinib could inhibit MK differentiation and platelet biogenesis and might be an agent for thrombocythemia.
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