BH3 Profiling – A Predictive Biomarker for Apoptotic Response to Chemotherapy

During oncogenesis, cancer cells provoke death signals due to a variety of aberrant behaviors, including genomic instability, oncogene activation, and anoikis. In order to grow and persist as clinically relevant tumors, cancer cells must find a way to escape pro-death signals in the intrinsic or mitochondrial apoptotic pathway. We have developed a tool, BH3 profiling, which can detect how cancer cells evade apoptosis. Some evade apoptosis, but become dependent on anti-apoptotic proteins like BCL-2. Such tumors are sensitive to agents like ABT-737 that target BCL-2, including acute lymphoblastic leukemia. BH3 profiling can also be used to detect how close a cancer cell is to reaching its apoptotic threshold. We find that "primed" cells that exist quite close to this threshold are easier to kill with apoptosis-inducing chemotherapy, whereas those that exist farther from this threshold are harder to kill. We can thus use BH3 profiling to predict response to chemotherapeutic agents in cancer cell lines in vitro. More compellingly, we also find that we can also predict clinical response to chemotherapeutic agents in cancer patients in vivo.