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

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

Abstract excerpt

Trastuzumab resistance limits the treatment of HER2-positive breast cancer. Here, we identify protein tyrosine phosphatase 1B (PTP1B) as a survival dependency in models of intrinsic and acquired trastuzumab resistance, including cells with endogenous ERBB2 kinase domain mutations (L755S and V777L), a patient-derived tumor organoid model, and orthotopic xenografts. PTP1B expression was elevated in multiple trastuzumab-resistant models, accompanied by increased PI3K-AKT and ERK signaling in several of these. The PTP1B inhibitor DPM-1003 suppressed growth of trastuzumab-resistant cells and organoids, inhibited xenograft progression, and induced apoptosis. Genetic ablation of PTP1B reduced growth and restored trastuzumab responsiveness in multiple resistance models, although JIMT1 cells remained resistant. Quantitative phosphoproteomics, phosphotyrosine immunoprecipitation, and substrate-trapping assays identified cofilin-1 (CFL1) and HSP90 as substrates of PTP1B. Loss of PTP1B increased their tyrosine phosphorylation, reduced their abundance, and increased their recovery in ubiquitin pull-downs. Proteasome inhibition restored substrate abundance, and PTP1B re-expression restored protein levels in PTP1B-null cells. These findings support a model in which PTP1B-dependent dephosphorylation limits turnover of the substrates CFL1 and HSP90. Genetic or pharmacological targeting of PTP1B suppressed survival-associated signaling and increased apoptotic markers. Together, these results identify PTP1B as a therapeutic vulnerability in trastuzumab-resistant HER2-positive breast cancer and implicate regulation of CFL1 and HSP90 abundance in the accompanying signaling response.