Overcoming On-Target Resistance to Tyrosine Kinase Inhibitors in Lung Cancer

Abstract

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.