Sunitinib causes thrombocytopenia by suppressing megakaryocyte proliferation

Sunitinib is associated with a higher incidence of thrombocytopenia than other molecularly targeted drugs. However, the underlying mechanism remains unclear. Because platelets are derived from megakaryocytes originating from hematopoietic progenitor cells in the bone marrow, sunitinib is presumed to interfere with megakaryocyte proliferation, maturation, or platelet production. Therefore, megakaryocytes play a crucial role in elucidating the mechanism of sunitinib-induced thrombocytopenia. However, in vivo sampling of megakaryocytes is challenging due to the invasiveness of bone marrow collection and the limited cell yield. Accordingly, we investigated the mechanism of thrombocytopenia induced by sunitinib and its active metabolite, N-desethyl sunitinib, using human induced pluripotent stem cell-derived immortalized megakaryocyte cell lines (imMKCLs). Both sunitinib and N-desethyl sunitinib suppressed the proliferation and cell division of imMKCLs. Furthermore, RNA sequencing revealed downregulation of cell cycle-related genes. Although the expression of cyclin-dependent kinase inhibitors, CDKN1A and CDKN1B, was significantly increased, polyploidization in imMKCLs remained unaffected. In conclusion, sunitinib and N-desethyl sunitinib induce thrombocytopenia by inhibiting the proliferation of immature megakaryocytes through suppression of cell cycle progression.