Dynamic BH3 profiling predicts therapeutic response and identifies optimal treatments.

  • Major finding: Dynamic BH3 profiling predicts therapeutic response and identifies optimal treatments.

  • Approach: Dynamic BH3 profiling measures changes in early death signaling in response to drug treatment.

  • Impact: This functional approach is a potential rapid-response tool for personalized cancer therapy.

Biomarkers that predict patient response to anticancer therapy have yet to be identified in most cases. Efforts to identify biomarkers have largely focused on tumor genotype and lack measurement of functional responses to perturbations in cancer cells. Montero and colleagues developed a rapid-response platform in which isolated cancer cells were treated with a panel of chemotherapeutic agents and assessed for early changes in mitochondrial priming, or apoptotic sensitivity, in response to treatment. This technique, named Dynamic BH3 Profiling (DBP), effectively predicted response to therapy in both cell lines and clinical samples. As a proof of principle, non–small cell lung cancer and breast cancer cell lines with varying therapeutic resistances were treated with a panel of tyrosine kinase inhibitors. By 16 hours post-treatment, an increase in BH3 peptide–induced mitochondrial depolarization was detected in sensitive cell lines, indicative of an increase in priming, and significantly correlated with increased apoptosis at 72 hours post-treatment, supporting the hypothesis that early induction of death signaling predicts the cytotoxic response to drug days later. In addition, DBP was capable of identifying the optimal kinase inhibitor that induced the greatest cytotoxicity in both hematologic cancer and solid tumor cell lines in vitro as well as in a mouse melanoma allograft model in vivo, demonstrating its power across multiple tumor lines and a wide range of inhibitors, including drug combinations. Furthermore, DBP of primary patient cells distinguished clinical sensitivity and resistance to imatinib in patients with chronic myelogenous leukemia and predicted progression-free survival in patients with ovarian adenocarcinoma treated with carboplatin, indicating that short-term analysis of clinical samples via DBP may stratify patients most likely to respond to therapy. Overall, these data establish DBP as a useful tool to rapidly predict patient response to therapy and suggest that DBP may be exploited as a biomarker to guide individual patient treatment.

Montero J, Sarosiek KA, DeAngelo JD, Maertens O, Ryan J, Ercan D, et al. Drug-induced death signaling strategy rapidly predicts cancer response to chemotherapy. Cell 2015;160:977–89.

Note:Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.