Command Palette

Search for a command to run...

Preprint WatchMildOctober 29th, 2026

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

Brown, E.; Jensen, P.; Yang, C.-H.; Cortes Sanchez, E.; Chu, Z.; Yang, H.; Qiao, Y.; Golkowski, M.; Srivastava, A.; Welm, B.; Fornetti, J.; Welm, A. L.

Response to SMAC mimetics across 69 breast cancer patient-derived xenograft organoid lines depends on RIPK1 activation, identifying a determinant of sensitivity to IAP antagonism in triple-negative breast cancer.

Mild contradiction

1 prior failure

One documented clinical failure (Phase 1 or 2) overlaps with the claimed mechanism.

The one BIRC2 entry in Claidex is tolinapant in peripheral T-cell lymphoma, stopped at Phase 1 on tolerability (tolinapant-birc2-iap-peripheral-t-cell-lymphoma-phase1-tolerability-termination). IAP antagonists have carried a persistent problem of unselected administration, and this preprint supplies a candidate selection marker in the form of RIPK1 activation competence. The relevance to the recorded failure is indirect, since that program ended on tolerability rather than on a response readout, but a sensitivity marker changes the benefit side of the same benefit-risk calculation. A narrower, marker-selected population is the most plausible route to a tolerable therapeutic index for this class.

Abstract excerpt

Triple-negative breast cancer (TNBC) is a highly metastatic and aggressive breast cancer subtype with limited targeted treatment options. Second mitochondrial activator of caspases (SMAC) mimetics represent a promising therapeutic class for TNBC patients, although they have yet to be approved clinically. Screening a repository of 69 breast cancer patient-derived xenograft organoid (PDxO) lines revealed that approximately 39% were sensitive to the SMAC mimetic birinapant. To define the basis of resistance in lines that did not respond, we compared birinapant-sensitive (S-) and de novo resistant (R-) TNBC PDxOs. Birinapant caused degradation of inhibitor of apoptosis proteins (IAPs) in both groups but failed to induce cell death in R-PDxOs. We determined that R-PDxOs were susceptible to certain types of apoptosis but were specifically resistant to TNFR-mediated cell death, an integral pathway involved in SMAC mimetic response. Moreover, RIPK1 activation via autophosphorylation, a critical event in TNFR-mediated apoptosis, was absent in both R-PDxOs and PDxOs selected for acquired birinapant resistance. Pharmacologic inhibition or degradation of RIPK1 protected S-PDxOs from birinapant-induced cell death, demonstrating that RIPK1 activation is required for response in TNBC. To investigate how to restore RIPK1 activation in R-PDxOs, we discovered that HOIP, an E3 ubiquitin ligase that inhibits RIPK1 autophosphorylation, was more abundant in R-PDxOs compared to S-PDxOs. Inhibiting HOIP activity restored RIPK1 autophosphorylation and sensitized a subset of R-PDxOs to birinapant. Together, these findings identify impaired RIPK1 autophosphorylation as a mechanism of birinapant resistance in TNBC and suggest that RIPK1 activation state may distinguish SMAC mimetic-sensitive and -resistant tumors. Targeting HOIP may provide a strategy to overcome resistance in selected tumors.

Matching Claidex post-mortems

1 of 1 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.