Strategies to overcome resistance mutations of Bruton's tyrosine kinase inhibitor ibrutinib

Ibrutinib, as the first Bruton's tyrosine kinase (Btk) inhibitor, has been shown to have clinically significant activity in leukemias and lymphomas. However, the initially responsive tumors will develop resistance during the process of treatment in few patients. Here, we summarized the mechanism of acquired resistance and suggested the next-generation Btk inhibitors that override the target resistance. Moreover, the development of combination of selective antagonists or inhibitors targeting to multiple protein kinases have increased therapeutic potency to reduce the risk of the emergence of kinases inhibitor resistance. Thus, the reported combination of therapeutic drugs as an alternative therapy to overcome ibrutinib collapse or reduce the risk of the emergence of Btk inhibitor resistance also has been reviewed.