Dynamic Reprogramming of the Kinome in Response to Targeted MEK Inhibition in Triple-Negative Breast Cancer

Kinase inhibitors have limited success in cancer treatment because tumors circumvent their action. Using a quantitative proteomics approach, we assessed kinome activity in response to MEK inhibition in triple-negative breast cancer (TNBC) cells and genetically engineered mice (GEMMs). MEK inhibition caused acute ERK activity loss, resulting in rapid c-Myc degradation that induced expression and activation of several receptor tyrosine kinases (RTKs). RNAi knockdown of ERK or c-Myc mimicked RTK induction by MEK inhibitors, and prevention of proteasomal c-Myc degradation blocked kinome reprogramming. MEK inhibitor-induced RTK stimulation overcame MEK2 inhibition, but not MEK1 inhibition, reactivating ERK and producing drug resistance. The C3Tag GEMM for TNBC similarly induced RTKs in response to MEK inhibition. The inhibitor-induced RTK profile suggested a kinase inhibitor combination therapy that produced GEMM tumor apoptosis and regression where single agents were ineffective. This approach defines mechanisms of drug resistance, allowing rational design of combination therapies for cancer. [Display omitted] ► Inhibition of the MEK-ERK pathway rapidly reprograms kinome activity in tumors ► c-Myc degradation induces expression and activation of receptor tyrosine kinases ► Receptor tyrosine kinase activation overcomes MEK inhibition, causing resistance ► Kinome inhibitor response profiling rationally predicts combination therapies Chemical proteomics reveals the dynamic rewiring of kinase networks in response to treatment with MEK inhibitors, uncovering how resistance to these inhibitors emerges in tumors and highlighting combination therapy approaches for bypassing drug resistance.