Abstract B23: Reprogramming of the cancer kinome in response to targeted kinase inhibition

Abstract Kinases are members of a large dynamic and cooperative signaling network, which senses inhibition of key nodal kinases and induces compensatory responses that offset pharmacological intervention. Combination therapies that target multiple growth- and survival promoting kinases are proving to be a better strategy for successful cancer therapy. What is lacking is the ability to measure whole kinome activity and to assess kinome adaptation and resistance to targeted therapies. We have developed a chemical proteomics approach that couples kinase affinity capture with quantitative mass spectrometry, providing a systems biology platform to profile global kinome activity in cancer cells, GEMM tumors and patient biopsies. Our chemical proteomic approach captures the majority of the expressed kinome estimated by RNA-seq and detects altered kinome activity profiles in response to stimulus or kinase inhibitors. Kinases from all major kinome subfamilies are captured with a large percentage representing the understudied kinome. For example, we discovered previously undefined activation of tyrosine and serine/threonine kinases in breast cancer cell lines in response to targeted kinase inhibitors that are currently in clinical trials. Combined kinome activity assessment using chemical proteomics and RNAi synthetic lethal screens predicted a specific kinase inhibitor combination therapy. The combination therapy gave apoptosis and tumor regression in a breast cancer GEMM, where single agents were largely ineffective. Thus we predicted an effective combination therapy based on assessment of kinome response to treatment of cells with drug.