The impact of SBF2 on taxane-induced peripheral neuropathy

Taxane-induced peripheral neuropathy (TIPN) is a devastating survivorship issue for many cancer patients. In addition to its impact on quality of life, this toxicity may lead to dose reductions or treatment discontinuation, adversely impacting survival outcomes and leading to health disparities in African Americans (AA). Our lab has previously identified deleterious mutations in SET-Binding Factor 2 (SBF2) that significantly associated with severe TIPN in AA patients. Here, we demonstrate the impact of SBF2 on taxane-induced neuronal damage using an ex vivo model of SBF2 knockdown of induced pluripotent stem cell-derived sensory neurons. Knockdown of SBF2 exacerbated paclitaxel changes to cell viability and neurite outgrowth while attenuating paclitaxel-induced sodium current inhibition. Our studies identified paclitaxel-induced expression changes specific to mature sensory neurons and revealed candidate genes involved in the exacerbation of paclitaxel-induced phenotypes accompanying SBF2 knockdown. Overall, these findings provide ex vivo support for the impact of SBF2 on the development of TIPN and shed light on the potential pathways involved. Taxanes, including paclitaxel, are cancer therapy agents that are widely used with curative potential. However, one of the most common side effects of taxanes, taxane-induced peripheral neuropathy (TIPN), is a devastating survivorship issue for many cancer patients. The employment of taxanes in chemotherapeutic regimens is limited by the severity of TIPN, which may cause lifelong debilitating pain and lack of sensation. Traditionally, African American women have reported higher rates of severe neuropathy with paclitaxel treatment, which has impacted their health outcomes negatively and contributed to treatment disparities. We have previously identified the association of developing severe TIPN with gene SBF2, which is a gene known for causing an inherited neuropathy, Charcot-Marie-Tooth disease type 4B2. In this study, we demonstrated that lower expressions of SBF2 impacted the neuronal morphologic and functional changes resultant from paclitaxel treatment. Moreover, we highlighted candidate genes and inflammatory molecular pathways as potential contributors to the progression of TIPN for future therapeutic target developments.