Paclitaxel-mediated secretion of inflammatory mediators, including TNFα, potentially creates paracrine and autocrine loops that can contribute to survival and reduction of paclitaxel-induced apoptosis in cancer cells.
One of the mechanisms of cancer cell survival is the expression of inhibitor of apoptosis proteins (IAPs). Cellular IAP (cIAP) is involved in inflammatory pro-survival NF-B activation, blocking the activation of the effector caspases 3 and 7, while X-linked IAP (XIAP) directly binds the effector caspases 3, 7 and 9, inhibiting the full activation of the apoptosis pathway.
ASTX660, a fragment-derived small molecule that is orally bioavailable, is a dual antagonist of cIAP and XIAP (Chessari 2014). Its inhibitory activity has been demonstrated in preclinical models of melanoma and other types of cancer, in which inflammation was present. It is currently being investigated in a single-agent Phase I/II clinical trial in patients with advanced solid tumors and lymphomas (NCT02503423).
Here, we characterize the activity of ASTX660 in preclinical models of triple-negative breast cancer (TNBC) as a single agent and in combination with paclitaxel whose inflammatory properties are hypothesized to sensitize the cells to ASTX660.
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