Editors' ChoiceCancer

From signaling knowledge to personalized therapy

Sci. Signal.  10 Mar 2015:
Vol. 8, Issue 367, pp. ec52
DOI: 10.1126/scisignal.aab0676

As Chief Scientific Editor Michael Yaffe has noted, a missing link in our ability to effectively treat cancer is information about the signaling pathways within the patient’s cancer cells. Using knowledge of the BCL-2 family of proteins with BH3 domains that regulate a cell’s sensitivity to stimuli that promote or “prime” cells to die by apoptosis, Monetero et al. developed a method called Dynamic BH3 Profiling (DBP) to assess priming in cancer cells, cell lines or patient tumor cells in response to various chemotherapeutic agents. Initial studies performed with non-small cell lung cancer cell lines with known resistance or sensitivity to specific drugs showed a positive correlation between the ability of specific drugs to prime the cells for death, as measured by the amount of mitochondrial membrane permeability triggered by proapoptotic BH3 peptides applied after exposure to the drug, and subsequent cell death days later. DBP also predicted drug cytotoxicity in breast cancer cell lines and multiple blood cancer cell lines. In a mouse melanoma allograft model, DBP analysis of the mouse melanoma cells, which had specific mutations affecting sensitivity to targeted therapies, to different kinase-targeted drugs singly or in combination predicted the combinations that were most effective at shrinking the tumors in vivo. DBP accurately sorted chronic myelogenous leukemia cells into those from patients that were sensitive to a drug that inhibits the kinase ABL and those that were resistant, establishing proof of principle in human cancer samples. DBP analysis of cell suspensions made from ovarian cancers showed that those patients with cells that exhibited robust priming had a longer progression-free survival period than those with cells that were less sensitive to BH3 peptide-induced priming. Thus, DBP shows the power of applying signaling knowledge to develop assays that can predict the most effective combination therapies, stratify patients into responding and nonresponding groups, and predict those patients who will most likely need additional treatment. DBP provides an important advance in precision medicine and personalized cancer therapy.

J. Montero, K. A. Sarosiek, J. D. DeAngelo, O. Maertens, J. Ryan, D. Ercan, H. Piao, N. S. Horowitz, R. S. Berkowitz, U. Matulonis, P. A. Jänne, P. C. Amrein, K. Cichowski, R. Drapkin, A. Letai, Drug-induced death signaling strategy rapidly predicts cancer response to chemotherapy. Cell 160, 977–989 (2015). [PubMed]