Mitochondrial Bcl2 Family Dynamics Define Therapy Responsiveness and Post Relapse-therapy Resistance in High-risk Pediatric Neuroblastomas

Neuroblastoma is a highly lethal pediatric solid tumor of the sympathetic nervous system. Patients often relapse after an initial response to therapy with tumors that are no longer sensitive to currently available cancer drugs. This is the major reason for treatment failure and death from neuroblastoma, yet how the cells become resistant to treatment remains poorly understood.

Apoptosis (or programmed cell death) occurs in cancer cells in response to diverse stressors, including exposure to chemotherapy or radiation therapy. This process is largely mediated by a mitochondrial apoptotic pathway regulated by a family of related proteins called the Bcl2 family. Many cancers repress these apoptotic signals at the mitochondria through alterations in their Bcl2 proteins that make them less responsive to stress.

Michael D. Hogarty, MD, and researchers at the Center for Childhood Cancer Research found that neuroblastomas are initially dependent upon either Bcl2 itself or the related Mcl1 protein to evade apoptosis, but never both. 

Mitochondrial profiling performed on a diverse array of neuroblastomas facilitated this discovery. Beyond identifying selective Bcl2 and Mcl1-dependent tumors, it was found that a third group of tumors were resistant to almost all stressors. These were the tumors that had relapsed after treatment, and this stress insensitivity mimics the extreme treatment resistance acquired by these tumors.

Additional experiments have confirmed that Bcl2-dependent neuroblastomas were highly sensitive to a Bcl2 inhibitor drug called venetoclax, whereas the Mcl1-dependent tumors were not. Bcl2 inhibitors may be useful in the clinical treatment of Bcl2-dependent neuroblastomas, but the Mcl1-dependent tumors will require alternative approaches. Using the mitochondrial profiling platform researchers have identified novel approaches to inhibiting Mcl1 that might provide leads for new drug development for this group.

Most importantly, these studies have identified a common feature of highly resistant neuroblastoma cells that implicates defective mitochondrial signaling. This provides a new platform for studying therapy resistance, and studies are ongoing to identify possible therapies that might convert a resistant cell back to a cell that is capable of activating apoptosis (and dying) when a cancer treatment is provided.

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