Response to SMAC mimetics in patient-derived models of triple-negative breast cancer relies on RIPK1 activation

Birinapant response in triple-negative breast cancer patient-derived xenograft organoid lines depends on RIPK1 autophosphorylation, with ~39% of 69 lines sensitive.

• Why it matters: SMAC mimetics are promising for TNBC but resistance limits their clinical use; the study addresses which signaling events determine sensitivity versus de novo resistance.
• What they did: The authors screened 69 TNBC PDxO lines for birinapant sensitivity, compared sensitive versus de novo resistant organoids, and tested whether RIPK1 activation and HOIP control birinapant-induced death.
• The result: RIPK1 activation was absent in de novo resistant and acquired-resistant PDxOs, and RIPK1 inhibition protected sensitive lines; HOIP inhibition restored RIPK1 autophosphorylation and sensitized a subset of resistant PDxOs.