Mapping phospho-catalytic dependencies of therapy-resistant tumors reveals new actionable vulnerabilities

A key to successful therapy is the identification of critical aberrant signaling networks whose inhibition would result in system failure of diseased cells. We have developed an innovative biotechnology pipeline to explore kinase-signaling networks in cell models and patient tissues. This high throughput kinase-activity mapping (HT-KAM) system uses peptide libraries as combinatorial sensors to reveal the identity and activity of kinases. This versatile strategy provides access to a vastly unexplored yet highly valuable molecular parameter with considerable potential to innovate the discovery of actionable kinase enzymes for precision medicine. After providing examples of newly found cooperative mechanisms of therapeutic resistance in BRCA^deficient triple-negative breast cancer and in BRAF^V600E melanoma and colorectal tumors that lead us to design new and more effective combinatorial targeted therapy treatments translatable in patients, I will discuss how the systematic mapping of phospho-catalytic circuits could help identify druggable dependencies that drive immunoevasion of persistent senescent cells in chemotherapy-resilient tumors or in dysfunctional aging tissues.
A key to successful therapy is the identification of critical aberrant signaling networks whose inhibition would result in system failure of diseased cells. We have developed an innovative biotechnology pipeline to explore kinase-signaling networks in cell models and patient tissues. This high throughput kinase-activity mapping (HT-KAM) system uses peptide libraries as combinatorial sensors to reveal the identity and activity of kinases. This versatile strategy provides access to a vastly unexplored yet highly valuable molecular parameter with considerable potential to innovate the discovery of actionable kinase enzymes for precision medicine. After providing examples of newly found cooperative mechanisms of therapeutic resistance in BRCA^deficient triple-negative breast cancer and in BRAF^V600E melanoma and colorectal tumors that lead us to design new and more effective combinatorial targeted therapy treatments translatable in patients, I will discuss how the systematic mapping of phospho-catalytic circuits could help identify druggable dependencies that drive immunoevasion of persistent senescent cells in chemotherapy-resilient tumors or in dysfunctional aging tissues.
A key to successful therapy is the identification of critical aberrant signaling networks whose inhibition would result in system failure of diseased cells. We have developed an innovative biotechnology pipeline to explore kinase-signaling networks in cell models and patient tissues. This high throughput kinase-activity mapping (HT-KAM) system uses peptide libraries as combinatorial sensors to reveal the identity and activity of kinases. This versatile strategy provides access to a vastly unexplored yet highly valuable molecular parameter with considerable potential to innovate the discovery of actionable kinase enzymes for precision medicine. After providing examples of newly found cooperative mechanisms of therapeutic resistance in BRCA^deficient triple-negative breast cancer and in BRAF^V600E melanoma and colorectal tumors that lead us to design new and more effective combinatorial targeted therapy treatments translatable in patients, I will discuss how the systematic mapping of phospho-catalytic circuits could help identify druggable dependencies that drive immunoevasion of persistent senescent cells in chemotherapy-resilient tumors or in dysfunctional aging tissues.

SELECTED REFERENCES

1. Olow A^#, Chen Z^#, Niedner RH, Wolf DM, Yau C Pankov A, Lee ‎EPR, Brown-Swigart L, van ‘t Veer LJ, Coppé JP. An atlas of the human kinome reveals the mutational landscape underlying dysregulated phosphorylation cascades in cancer. (2016) Cancer Research 76(7): 1733-45. PMID: 26921330
2. Coppé JP *, Mori M, Pan B, Yau C, Wolf DM, Ruiz-Saenz A, Brunen D, Prahallad A, Cornelissen-Steijger P, Kemper K, Posch C, Wang C, Dreyer CA, Krijgsman O, Lee PRE, Chen Z, Peeper DS, Moasser MM, Bernards R, van ‘t Veer LJ. Mapping phospho-catalytic dependencies of therapy-resistant tumors reveals actionable vulnerabilities. (2019) Nature Cell Biology. 21(6): 778-790. PMID: 31160710    * corresponding author
3. Muñoz DP^#, Yannone SM^#, Daemen A, Yu Sun Y, Vakar-Lopez F, Kawahara M, Freund AM, Rodier F, Wu JD, Desprez PY, Raulet DH, Nelson PS, van ’t Veer LJ, Campisi J, Coppé JP. Targetable mechanisms driving immunoevasion of persistent senescent cells link chemotherapy-resistant cancers to aging. (2019) Journal of Clinical Investigation insight. 4(14): e12476. PMID: 31184599
4. Atreya CE and Coppé JP (co-PIs). Kinome-guided targeting of cooperative dependencies in BRAF and KRAS mutated colorectal cancer. 06/01/2019 – 05/30/2025. NIH/NCI R01 CA229447-01