Articles Related to Iwai K
Mechanisms of Resistance to Kinase Inhibitors and Strategies to Prevent the Development of Drug Resistance
Targeting mutant proteins and associated signaling pathways of driver oncogenes by small molecule kinase inhibitors (KIs) are a
promising strategy of cancer therapy. However, despite the initial success of treatment, KIs often become ineffective as intrinsic and
acquired resistance. This article reviews the English-language literature to explore the underlying mechanisms of drug resistance and
to present a challenge for developing drugs to overcome resistance. Mechanisms of acquired resistance include 1) the selection of
pre-existing subclones with other mutations, 2) the emergence of secondary mutations in the target kinase domain, 3) upregulation
of kinases both within the same kinase family and their related kinase families, as well as activation of alternative bypass pathways, 4)
epithelial-mesenchymal transition, 5) overexpression of pro-survival Bcl-2 family proteins and 6) drug efflux mechanisms. Currently
available methods are to obtain tumor biopsy samples at recurrence or progression if the tumor lesion is accessible to a biopsy and to
use the second- and third-generation KIs based on the individual need of each patient. Furthermore, recent computational challenges
provide design principles to prevent the development of drug resistance. In conclusion, we provide an overview of the postulated
resistance mechanisms and highlight the future direction of computational structure-based design of new potent KIs.