Overcoming Resistance to HER2 Inhibitors Through State-Specific Kinase Binding

The heterodimeric receptor tyrosine kinase complex formed by HER2 and HER3 can act as an oncogenic driver and is also responsible for rescuing a large number of cancers from a diverse set of targeted therapies. Current inhibitors of these proteins, particularly HER2, have dramatically improved patient outcomes in the clinic but recent studies have demonstrated that stimulation of the heterodimeric complex, either by growth factors or increasing the concentrations of HER2 and HER3 at the membrane, significantly diminishes their activity. In order to find an inhibitor of the active HER2/HER3 oncogenic complex we developed a panel of Ba/F3 cell lines suitable for ultra-high throughput screening. Medicinal chemistry on the hit scaffold resulted in a novel inhibitor that acts through the preferential inhibition of the active state of HER2 and as a result is able to overcome cellular mechanisms of resistance such as growth factors or mutations that stabilize the active form of HER2.