Pharmacological inhibition of transforming growth factor-β activated kinase 1 (TAK1) prevents chemotherapy induced peripheral neuropathy (CIPN)

The development of chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting side effect of many neurotoxic chemotherapeutics where up to 30-40% of patients develop neuropathy. Traditionally, chemotherapeutics such as paclitaxel exert their anti-cancer effects by stabilizing microtubules, effectively inhibiting cell division and promoting apoptosis in cancer cells. However, data suggest that paclitaxel may also activate toll-like receptor 4 (TLR4) through off-target affinity, inducing neuroinflammation. Transforming growth factor beta-activated kinase 1 (TAK1) is a key signaling node in the TLR4 inflammatory pathway and has previously been shown to regulate inflammation and pain. Here, our group evaluated the therapeutic potential of the selective and potent TAK1 inhibitor, HS-276, to attenuate paclitaxel- and oxaliplatin-induced inflammation and mechanical allodynia. Our studies evaluated in vitro phosphorylated TAK1 activity following paclitaxel treatment in human peripheral blood mononuclear cells (PBMC's) as well as cytokine responses. In a paclitaxel mouse model of CIPN, assessment of both static and dynamic tactile allodynia using behavioral responses to punctate and dynamic brush stimulation were evaluated in mice receiving either HS-276, gabapentin or vehicle treatment. Further validation of HS-276 was also assessed in an oxaliplatin CIPN mouse model. Our findings support that TAK1 inhibition blocked the induction of phosphorylated TAK1 following paclitaxel treatment in PBMC's as well as the expression pro-inflammatory cytokines such as TNF, IL-6, and IL-1β. In the paclitaxel and oxaliplatin CIPN mouse model, administration of HS-276 significantly reduced mechanical allodynia comparable to gabapentin. Overall, our results support that TAK1 is a novel regulator of paclitaxel- and oxaliplatin-induced CIPN. PERSPECTIVE: This manuscript demonstrates the therapeutic potential of TAK1-targeted therapies for the treatment of chemotherapy-induced peripheral neuropathy (CIPN). This new treatment has the potential to protect CIPN patients from development of debilitating and dose-limiting CIPN-associated pain, and allow patients to remain on life-saving chemotherapeutic treatments for longer.