SHP2 Inhibition Enhances the Effects of Tyrosine Kinase Inhibitors in Preclinical Models of Treatment-naïve <i>ALK-, ROS1-</i> , or <i>EGFR</i> -altered Non–small Cell Lung Cancer

Abstract

After molecular-targeted therapy, some cancer cells may remain that are resistant to therapies targeting oncogene alterations, such as those in the genes encoding the <i>EGFR</i> and anaplastic lymphoma kinase (<i>ALK</i>) as well as c-ros oncogene 1 (<i>ROS1</i>). The mechanisms underlying this type of resistance are unknown. In this article, we report the potential role of Src homology 2 domain-containing phosphatase 2 (SHP2) in the residual cells of <i>ALK</i>/<i>ROS1</i>/<i>EGFR-</i>altered non-small cell lung cancer (NSCLC). Molecular-targeted therapies failed to inhibit the ERK signaling pathway in the residual cells, whereas the SHP2 inhibitor SHP099 abolished their remaining ERK activity. SHP099 administered in combination with molecular-targeted therapy resulted in marked growth inhibition of cancer cells both <i>in vitro</i> and <i>in vivo</i> Thus, treatment combining an SHP2 inhibitor and a tyrosine kinase inhibitor may be a promising therapeutic strategy for oncogene-driven NSCLC.