PTP1B supports survival and regulates CFL1 and HSP90a abundance in trastuzumab-resistant HER2-positive breast cancer.

PTP1B is a survival dependency in intrinsic and acquired trastuzumab-resistant HER2-positive breast cancer models, and its inhibition with DPM-1003 suppresses growth and induces apoptosis.

• Why it matters: Trastuzumab resistance limits treatment, and the work addresses the need to identify actionable vulnerabilities and the signaling mechanisms sustaining resistant tumor survival.
• What they did: The study used intrinsic and acquired resistance models, including ERBB2 L755S and V777L mutant cells, a patient-derived tumor organoid model, and orthotopic xenografts, plus phosphoproteomics and substrate-trapping to map PTP1B substrates.
• The result: PTP1B targeting reduced survival-associated signaling and increased apoptotic markers, while PTP1B loss increased tyrosine phosphorylation and reduced abundance of CFL1 and HSP90, implicating PTP1B-dependent dephosphorylation in their turnover.