Science and Technology Production
Article
Authorship
Virginia Judith Wolos
;
Giulia Rocca
;
Marianela Abrigo
;
Marcela Solange Villaverde
;
Ezequiel Lacunza
;
Carla Pulero
;
Georgina Alexandra Cardama
;
Giorgio Arrigoni,
;
FISZMAN, GABRIEL LEON
Date
2026
Publishing House and Editing Place
PERGAMON-ELSEVIER SCIENCE LTD
Magazine
LIFE SCIENCES
PERGAMON-ELSEVIER SCIENCE LTD
Summary
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SIGEVA
Resistance to targeted therapy in HER2-positive breast cancer remains a clinicalchallenge, especially for patients with relapsed or metastatic disease. Particularly,persistent activation of hypoxia-inducible factor 1 (HIF-1) signalling is well documentedin the context of trastuzumab and trastuzumab emtansine resistance. To achieve adeeper understanding of how HIF-1 activity modulates the response to anti-HER2treatment, we functionally characterized a cellular model of hypoxia-induced drugresist...
Resistance to targeted therapy in HER2-positive breast cancer remains a clinicalchallenge, especially for patients with relapsed or metastatic disease. Particularly,persistent activation of hypoxia-inducible factor 1 (HIF-1) signalling is well documentedin the context of trastuzumab and trastuzumab emtansine resistance. To achieve adeeper understanding of how HIF-1 activity modulates the response to anti-HER2treatment, we functionally characterized a cellular model of hypoxia-induced drugresistance for HER2-positive breast cancer using shotgun proteomics. By globalphosphoproteomics profiling, the Rac1 pathway was identified as one of the mostenriched signalling networks under hypoxia. Furthermore, the selective Rac1 blockadewith the 1A-116 small-molecule inhibitor sensitised HER2-positive cells to trastuzumabin both 2D and 3D culture systems. Altogether, our findings demonstrate that hypoxicconditions induce the resistance of HER2-positive breast cancer cells to targetedtherapy and suggest the therapeutic potential of Rac1 inhibition to enhancetrastuzumab efficacy.
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Key Words
TRASTUZUMABRAC1BREAST CANCERHYPOXIAHER2