Targeted Therapy in Refractory Thyroid Cancer

Current Achievements and Limitations

Lucia Brilli; Furio Pacini

Disclosures

Future Oncol. 2011;7(5):657-668. 

In This Article

Resistance

An important limitation to the use of TKIs is that patients may be intrinsically resistant to treatment or may develop resistance during therapy.

Intrinsic resistance may be related to the mutational status of the receptors, rendering the cells insensitive to the drugs. This can occur in case of mutations that decrease the affinity of the drug for the target TK domain while maintaining its catalytic activity, or in case of mutations that alter the amino acids surrounding the binding site of the drug, thus decreasing the availability of the target region towards the inhibitors. Another possibility is that the mutation increases the affinity of the kinases for ATP, thus decreasing the effectiveness of the ATP competitive inhibitors.[17]

Acquired resistance occurs when a tumor escapes sensitivity to the drug by enhancing a pre-existing baseline expression of alternative proangiogenic pathways. In addition, resistance may derive from de novo mutation of the receptor, resulting in changes of its 3D structure and thus precluding the binding of the drug. Such mutations may occur in part of a metastatic lesion or in some, but not all, the lesions, thus explaining different degrees of response in different tissues.

Additional mechanism(s) involved in secondary resistance may be represented by chromosomal alterations, overexpression of the target protein, activation of alternative pathways, overexpression of multidrug resistance genes and changes in drug bioavailability.[46]

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