The SP1-SuperEnhancer-SPHK1 Axis Mediates Niraparib Resistance in TNBC

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• PARP inhibitors are effective against BRCA-mutated cancers but face limitations due to rare mutations and resistance.
• Triple-negative breast cancer (TNBC) presents unique challenges for PARP inhibitor therapy.
• Understanding resistance mechanisms is crucial for improving treatment efficacy.

Purpose of the Study:

• Investigate Niraparib's effect on sphingolipid metabolism and SPHK1 in TNBC.
• Elucidate a novel super-enhancer (SE)-mediated mechanism of Niraparib resistance.
• Utilize AI for compound screening to overcome Niraparib resistance.

Main Methods:

• Multi-omics analyses to identify molecular pathways.
• Investigated the role of transcription factor SP1 and super-enhancers.
• AI-based virtual screening for drug discovery.
• In vitro assays to validate findings and synergistic effects.

Main Results:

• Niraparib upregulates SPHK1 via the SP1-SE axis, leading to resistance in TNBC.
• SP1 inhibition by Niraparib enhances its binding to the SE, promoting SPHK1 expression.
• AI screening identified Echinatin as a potent SP1 inhibitor with synergistic effects with Niraparib.
• Echinatin showed a better toxicity profile compared to targeting SPHK1 directly.

Conclusions:

• Niraparib resistance is mediated by the SP1-SE-SPHK1 signaling axis.
• Echinatin effectively reverses Niraparib resistance by inhibiting SP1.
• This study proposes a novel combination therapy of Niraparib and Echinatin for TNBC.