Mutations/drug resistance kinase activation

Because of their rapid rate of cell division, cancer cells are also sometimes able to develop drug resistance. Imatinib (4.12) (Figure 4.13) is a kinase inhibitor for the treatment of certain types of leukemia. The x-ray crystal structure of imatinib bound in the active site of the kinase has been solved and shows how mutations in the enzyme interfere with binding and allow drug resistance.20... 

Fig. 13.2 Imatinib wrapping modification engineered to overcome drug resistance in the C-Kit kinase. This resistance is promoted by the somatic mutation Asp816Val. The mutation induces the dehydron Phe811-Ala814 in the activation loop which in turn can be targeted or wrapped by suitably modifying imatinib at the position highlighted by the rectangle [3]...

Although most patients will respond to Imatinib it is not curative as minimal residual disease can be detected at the molecular level in the bone marrow. Mutations within the kinase domain of Bcr-Abl which can inhibit drug binding is known to contribute to clinical resistance. Additional mechanisms of resistance include the activation of Bcr-Abl independent survival pathways and overexpression of drug transporters. Finally an active area of research is to determine the contribution of the microenvironment of the bone marrow were minimal residual disease is typically found. Determining whether specific soluble factors or extracellular matrixes produced by the bone marrow microenvironment contributes to imanitib resistance may lead to combination therapies targeting minimal residual disease within the bone marrow compartment. 

In this first proof of concept study, labeling the activation of clinically relevant tyrosine kinases with fluorophore allowed for the sensitive and reliable identification of DFG-out stabilizers from compound libraries. The identified hits and subsequent compound optimization illustrates a generic alternative rationale to overcome drug resistance by generating type II inhibitors that have the intrinsic ability to adapt to the binding site distortions induced by these mutations while also locking the kinase in an inactive conformation. 

Resistance to foscamet may result from mutation of viral DNA polymerase. Because this drug does not require phosphorylation for activation, thymidine kinase-deficient mutants should not be resistant to fos-carnet. 

Mechanisms and pharmacokinetics Cidofovir is activated exclusively by host cell kinases and inhibits DNA polymerases of HSV, CMV, adenovirus, and papillomavirus. Resistance is due to mutations in the DNA pol5merase gene. The drug has been used by intravenous and topical administration and by intravitreal injection. Cidofovir undergoes renal elimination in proportion to creatinine clearance. 

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