Co-targeting PARP and SHP2 Overcomes Resistance to Apoptosis and Induces Durable Responses in Breast Cancer.

TargetScore modeling in breast cancer cells identified drug-induced adaptive phospho-protein signaling, and PARP1/2 plus SHP2 co-targeting produced near-complete tumor eradication with durable responses in genetically engineered mouse models.

• Why it matters: Drug resistance often arises from therapy-triggered pro-survival signaling adaptations, limiting long-term effectiveness and making it hard to select precision combinations that block these rewired dependencies.
• What they did: Breast cancer cells were perturbed with inhibitors of anti-apoptotic mediators, especially MCL1, then analyzed with TargetScore network modeling and phosphoproteomics to track short-term (days) stress and long-term (months) acquired resistance.
• The result: TargetScore predicted concurrent activation of growth and DNA repair pathways, and validation showed strong in vitro and in vivo responses to PARP1/2 and SHP2 inhibitor combinations, with functional proteomics linking response to DNA damage response, replication stress, and cell cycle arrest.

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