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Advances in genomics, an improved understanding of malignant transformation, and the development of potent small molecule inhibitors capable of targeting key kinases have led to the adoption of genotype-guided approaches for the treatment of advanced cancers. As regulators of complex signaling networks, tyrosine kinases are among the most attractive targets. Moreover, insight into the conserved three-dimensional structures of these kinases and their mechanism of activation has facilitated the development of selective tyrosine kinase inhibitors (TKIs). TKIs have shown robust clinical activity in many different oncogene-addicted cancers; however, resistance invariably develops. In a significant proportion of patients, resistance results from acquired genetic alterations within the kinase target that allow cancer cells to escape TKI-mediated growth suppression. In this review, we discuss clinically observed and preclinical on-target resistance events in oncogene-driven solid tumors and describe current and future therapeutic strategies to overcome this type of resistance.
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