Seminar

Mapping the phospho-catalytic dependencies of therapy-resistant tumors reveals CDK vulnerabilities in BRAF(V600E) metastatic colorectal cancer

Jean-Philippe Coppé

Phosphorylation networks intimately regulate mechanisms of disease progression and response to therapy. Yet, mapping the phospho-catalytic profile of kinases in cells or tissues remains a challenge. My group has pioneered an innovative biochemical and analytical system to measure the functional state of kinase enzymes and their signaling circuits. Our technology (HT-KAM)1-5 and computational resources (PhosphoAtlas6 and network modeling methods) provide access to a vastly underexplored parameter with considerable potential to accelerate the discovery of actionable targets, kinases or otherwise, for functional precision medicine. Our team is particularly interested in the rational design of combination therapies to restore therapeutic response in relapsing/metastatic tumors, or to prevent the development of drug resistance in cancer patients. Here, I will concentrate on BRAF(V600E) metastatic colorectal cancer (mCRC), which is associated with worse CRC prognosis and limited treatment options. Using the high throughput kinase activity mapping (HT-KAM) platform, we probed the phospho-circuits of BRAF(V600E) mCRC tumors to elucidate how their kinome is dynamically reprogrammed in response to standard of care (SOC) therapy, i.e., BRAF+EGFR inhibition. We found that a paradoxical CDK1/2-dependent compensatory stress pathway orchestrating DNA-damage repair/chromatin-remodeling factors, causes resistance to SOC. Targeting this mechanism induces significant, durable suppression of tumor growth and tumor regression in patient-derived xenograft models. Clinical trial is under consideration. Based on results from an array of cancers we interrogate in our lab or in collaboration with other groups using our phospho-reactome mapping system, we are starting to gain a global understanding of how cancer cells systematically overcome therapeutic pressure by upregulating (and downregulating) specific sets of interdependent pathways that work in concert to coordinate tumor survival, escape immuno-surveillance, and promote malignant progression. Our goal is to leverage such precise knowledge to transform the discovery and implementation of effective treatment strategies to improve patients’ outcome.