RABL6A signaling as an oncogenic driver and therapeutic target in malignant peripheral nerve sheath tumors (MPNST)

Malignant peripheral nerve sheath tumors (MPNSTs) are deadly sarcomas that arise either spontaneously or in association with the hereditary cancer predisposition syndrome, Neurofibromatosis Type I (NF1). MPNSTs are the leading cause of death in the over two million patients around the world living with NF1. Sadly, current treatment with traditional chemotherapy and radiation is nonspecific, ineffective, and highly toxic. This highlights the need for a greater understanding of the key drivers of MPNSTs to develop more targeted, effective treatments.

We recently identified a crucial driver of MPNST development, called RABL6A, whose expression is extremely high in patient MPNSTs. My research showed that RABL6A works in part by inhibiting the retinoblastoma (RB1) tumor suppressor. We found drugs that reactivate RB1, called CDK inhibitors which are used to treat women with metastatic breast cancer, are effective at halting MPNST growth. However, resistance to this single therapy occurs rapidly. To combat drug resistance, we targeted a second cancer pathway dysregulated in MPNSTs that is also turned on by RABL6A – namely Ras-MEK signaling. Combination therapy was far superior to single drug treatment in a mouse model of MPNST and led to a marked reduction in tumor growth, including initial shrinkage of most lesions, and more than 3-fold extension in survival. While superior to treatment with single drugs, tumor regrowth still occurred during combination therapy. Those are called drug resistant tumors.

Development of drug resistance is one of the most pervasive clinical problems during cancer therapy, emphasizing the need to better understand what is driving these tumors. To gain insight into additional RABL6A-regulated pathways, we tested if RABL6A was necessary for MPNST development in mice. We found that removing RABL6A from tumors markedly slowed tumor growth and extended animal survival, likely due to its effects on RB1 and other powerful regulators of cancer we identified. Interestingly, while initial loss of RABL6A stunted tumor growth, sustained loss led to a resistance-like phenotype where other tumor-promoting pathways became upregulated. One of the factors turned on in tumors lacking RABL6A was Myc, a druggable oncoprotein whose inhibition is useful in halting other tumor types, like lymphoma. Such results provide another drug option that could be included in new combination therapies for MPNSTs.

then examined the role of RABL6A in the cells that give rise to MPNSTs, called Schwann cells. We found that RABL6A expression goes down as Schwann cells age and stop dividing, whereas depleting RABL6A from young, growing cells causes an abrupt halt to cell growth called senescence. Additional investigation revealed this induction of senescence depended on RABL6A's regulation of RB1, which we first noted in tumors. Together, our data suggest RABL6A expression is tightly regulated to promote proper Schwann cell biology; however, when signaling becomes awry, excessive RABL6A promotes malignant transformation.

Since we cannot target RABL6A directly with drugs (no inhibitors currently exist), we attempted to circumvent its effects by targeting downstream effectors, like CDK4/6 and MEK. My studies have culminated in identifying key RABL6A-regulated pathways that represent clinically relevant targets for therapy. Future studies will use the knowledge gained here to develop drug treatments for MPNST patients that are effective, targeted, and combat resistance.