Mandati, Vinay, Panepinto, Maria C, Felice, Christy, Krivitsky, Sean, Russo, Suzanne, Naik, Payal, Utama, Raditya, Spector, David L, Cifani, Paolo, Tonks, Nicholas K (October 2026) PTP1B supports survival and regulates CFL1 and HSP90α abundance in trastuzumab-resistant HER2-positive breast cancer. bioRxiv. ISSN 2692-8205 (Submitted)
Abstract
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 HSP90α 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 HSP90α. 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 HSP90α abundance in the accompanying signaling response. Significance PTP1B targeting suppresses growth of trastuzumab-resistant HER2-positive breast cancer models and implicates phosphatase-dependent control of substrate turnover as a potential mechanism supporting tumor cell survival and therapeutic resistance.
| Item Type: | Paper |
|---|---|
| Subjects: | diseases & disorders > cancer diseases & disorders diseases & disorders > cancer > cancer types > breast cancer diseases & disorders > cancer > cancer types |
| CSHL Authors: | |
| Communities: | CSHL labs > Beyaz lab CSHL labs > Fearon lab CSHL labs > Koo Lab CSHL labs > Spector lab CSHL labs > Tonks lab CSHL Cancer Center Shared Resources CSHL Cancer Center Shared Resources > Animal Services CSHL Cancer Center Shared Resources > Bioinformatics Service CSHL Post Doctoral Fellows |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 28 October 2026 |
| Date Deposited: | 05 Nov 2026 16:50 |
| Last Modified: | 05 Nov 2026 16:50 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/42359 |
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