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William J. Gradishar, MD, FACP, FASCO
William J. Gradishar, MD, FACP, FASCO
Posted: Thursday, April 11, 2024
For patients with HER2-positive breast cancer, a novel pathway involving protein tyrosine phosphatase 1B (PTP1B), ring finger protein 213 (RNF213), CYLD, and SPATA may regulate the extent of inflammatory cell death in hypoxic tumors, according to a study presented at the American Academy for Cancer Research (AACR) Annual Meeting 2024 (Abstract LB052/13). These findings provide evidence supporting the clinical benefit of targeting PTP1B inhibitors in hypoxic tumor cells by turning “cold” tumors into “hot” and increasing their susceptibility to immune-mediated destruction, suggested Benjamin G. Neel, MD, PhD, of New York University Langone Health Perlmutter Cancer Center, and colleagues.
“We found previously that PTP1B deficiency/inhibition promotes HER2-positive breast cancer cell death in hypoxia by activating RNF213,” explained Dr. Neel.
The study authors reported evidence supporting the reciprocal control of RNF213 phosphorylation on tyrosine-125 by both ABL1/2 and PTP1B. When phosphorylated, RNF213 oligomerizes, leading to the activation of the ubiquitin ligase domain RZ. Activation of the RZ domain results in the ubiquitination of CYLD/SPATA2, which is further targeted by the LUBAC complex to promote its degradation and activate NF-kB, according to the study authors. The combination of activated NF-kB and hypoxia-induced endoplasmic reticulum stress appears to lead to a subtype of inflammatory cell death known as GDSMD-dependent pyroptosis. Furthermore, the deletion of CYLD in HER2-positive cell-derived xenografts produces effects similar to that in cells with a PTP1B deficiency. Moreover, RNF213 knockout models demonstrated the impact of the RZ domain on PTP1B-dependent tumor cell death.
Disclosure: For full disclosures of the study authors, visit abstractsonline.com.
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