Abstract: Phosphorylation networks intimately regulate mechanisms of response to therapies. Yet, mapping the phospho-catalytic profile of kinases in cells or tissues remains a challenge. My lab has pioneered an innovative biochemical and analytical system to measure the functional state of kinase enzymes and their signaling circuits. Our technology and resource (named HT-KAM and PhosphoAtlas) provide access to an unexplored parameter with considerable potential to accelerate the discovery of actionable targets for functional precision medicine. Focusing on BRAF(V600E) metastatic colorectal cancer, we found mechanisms of intrinsic resistance to BRAF+EGFR inhibition in tumors, including the parallel compensatory activation of an auto-onco-crine COX2–SRC pathway that is clinically tractable and for which translation in clinical trial is under consideration. Furthermore, mapping the phospho-catalytic signatures of melanoma specimens identified RPS6KB1 and PIM1 as emerging druggable vulnerabilities predictive of poor outcome in BRAF(V600E) melanoma patients. Our results show that therapeutic resistance can be caused by the concerted upregulation of interdependent pathways. Our kinase activity-mapping system is a versatile strategy that innovates the exploration of actionable kinases for personalized medicine.

Selected References:
Olow and Chen, et al 2016 Cancer Research
Coppé, et al 2019 Nature Cell Biology
Kim, et al 2021 Science
Ruiz & Atreya, et al 2023 Nature Cancer
Chong, et al 2023 JCI
Feichtenschlager, et al 2024 Molecular Cancer

Biography: Dr. Coppé is an Associate Professor at UCSF. He received his PhD from UC Berkeley and the Lawrence Berkeley National Laboratory, where he studied cellular senescence, aging and cancer with Dr. Campisi. His group focuses on revealing the intracellular and extracellular molecular circuits that wire therapy-resistant tumors. He pioneered a kinome mapping system to measure the functional state of kinase enzymes and their signaling networks. His goal is to translate orthogonal modalities of treatment resistance into actionable vulnerabilities to restore therapeutic response and prevent treatment failure.