Receptor Tyrosine Kinase Phosphorylation Pattern-Based Multidrug Combination Is an Effective Approach for Personalized Cancer Treatment

Abstract

Receptor tyrosine kinases (RTK) are key signaling molecules in regulating cancer cell growth and are important cancer drug targets. Despite the success of specific RTK-targeting therapy in certain cancer treatments, the overall response rates are limited to the drug target-stratified populations. We have systematically studied RTK activations in a panel of cancer cell lines, primary cancers, and cancer xenografts and found that different combinations of RTKs were activated in different cancer cells regardless of their tissue origins. Combinations of specific RTK inhibitors (RTKi) preferentially inhibited proliferation of the cancer cells with corresponding RTK activation profiles. We also found that the activations of RTKs were regulated by both cell-autonomous and environment-dependent mechanisms and demonstrated that inhibition of all activated RTKs was essential to completely block cancer cell proliferation. In addition, c-Myc downregulation was identified as an indicator for the effectiveness of the RTKi combination treatments. Our findings demonstrated that the RTK activation profile is a valid biomarker for diagnosis and stratification of cancers, and a corresponding combination of RTKis is a promising strategy to treat cancers, particularly the single RTKi therapy-resistant cancers, selectively and effectively. Mol Cancer Ther; 15(10); 2508-20. ©2016 AACR.