2. Academic Validation
  3. HIV-protease inhibitors potentiate the activity of carfilzomib in triple-negative breast cancer

HIV-protease inhibitors potentiate the activity of carfilzomib in triple-negative breast cancer

  • Br J Cancer. 2024 Jul 5. doi: 10.1038/s41416-024-02774-9.
Andrej Besse 1 2,  Lenka Sedlarikova 3 2,  Lorina Buechler 1,  Marianne Kraus 1,  Chieh-Hsiang Yang 4 5,  Nicol Strakova 6 7,  Karel Soucek 6 8,  Jiri Navratil 9 10,  Marek Svoboda 9 10,  Alana L Welm 4 5,  Markus Joerger 11,  Christoph Driessen 1 11,  Lenka Besse 12 13
Affiliations

Affiliations

  • 1 Laboratory of Experimental Oncology, Department of Oncology and Hematology, Cantonal Hospital St. Gallen, St. Gallen, 9000, Switzerland.
  • 2 Department of Biology, Faculty of Medicine, Masaryk University, Brno, 62500, Czech Republic.
  • 3 Babak Myeloma Group, Department of Pathological Physiology, Masaryk University, Brno, 62500, Czech Republic.
  • 4 Department of Oncological Sciences, University of Utah, Salt Lake City, UT, USA.
  • 5 Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
  • 6 Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, 612 00, Czech Republic.
  • 7 Veterinary Research Institute, Brno, 62500, Czech Republic.
  • 8 International Clinical Research Center, St. Anne's University Hospital Brno, Brno, Czech Republic.
  • 9 Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, Brno, 62500, Czech Republic.
  • 10 Faculty of Medicine, Masaryk University, Brno, 62500, Czech Republic.
  • 11 Department of Oncology and Hematology, Cantonal Hospital St. Gallen, St. Gallen, 9000, Switzerland.
  • 12 Laboratory of Experimental Oncology, Department of Oncology and Hematology, Cantonal Hospital St. Gallen, St. Gallen, 9000, Switzerland. Lenka.besse@kssg.ch.
  • 13 Department of Biology, Faculty of Medicine, Masaryk University, Brno, 62500, Czech Republic. Lenka.besse@kssg.ch.
PMID: 38969867 DOI: 10.1038/s41416-024-02774-9
Abstract

Background: Resistance to chemotherapy is a major problem in the treatment of patients with triple-negative breast Cancer (TNBC). Preclinical data suggest that TNBC is dependent on proteasomes; however, clinical observations indicate that the efficacy of Proteasome inhibitors in TNBC may be limited, suggesting the need for combination therapies.

Methods: We compared bortezomib and carfilzomib and their combinations with nelfinavir and lopinavir in TNBC cell lines and primary cells with regard to their cytotoxic activity, functional Proteasome inhibition, and induction of the unfolded protein response (UPR). Furthermore, we evaluated the involvement of sXBP1, ABCB1, and ABCG2 in the cytotoxic activity of drug combinations.

Results: Carfilzomib, via Proteasome β5 + β2 inhibition, is more cytotoxic in TNBC than bortezomib, which inhibits β5 + β1 Proteasome subunits. The cytotoxicity of carfilzomib was significantly potentiated by nelfinavir or lopinavir. Carfilzomib with lopinavir induced endoplasmic reticulum stress and pro-apoptotic UPR through the accumulation of excess proteasomal substrate protein in TNBC in vitro. Moreover, lopinavir increased the intracellular availability of carfilzomib by inhibiting carfilzomib export from cells that express high levels and activity of ABCB1, but not ABCG2.

Conclusion: Proteasome inhibition by carfilzomib combined with nelfinavir/lopinavir represents a potential treatment option for TNBC, warranting further investigation.

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