Serine/threonine-protein kinase B-raf (BRAF) mutations are found in 8-15% of colorectal cancer patients and identify a subset of tumors with poor outcome in the metastatic setting. We have previously reported that BRAF-mutant human cells display a high rate of protein production, causing proteotoxic stress, and are selectively sensitive to the proteasome inhibitors bortezomib and carfilzomib. In this work, we tested whether carfilzomib could restrain the growth of BRAF-mutant colorectal tumors not only by targeting cancer cells directly, but also by promoting an immune-mediated antitumor response. In human and mouse colorectal cancer cells, carfilzomib triggered robust endoplasmic reticulum stress and autophagy, followed by the emission of immunogenic-damage-associated molecules. Intravenous administration of carfilzomib delayed the growth of BRAF-mutant murine tumors and mobilized the danger-signal proteins calreticulin and high mobility group box 1 (HMGB1). Analyses of drug-treated samples revealed increased intratumor recruitment of activated cytotoxic T cells and natural killers, concomitant with the downregulation of forkhead box protein P3 (Foxp3)(+) T-cell surface glycoprotein CD4 (CD4)T+ cells, indicating that carfilzomib promotes reshaping of the immune microenvironment of BRAF-mutant murine colorectal tumors. These results will inform the design of clinical trials in BRAF-mutant colorectal cancer patients.

Preclinical efficacy of carfilzomib in BRAF-mutant colorectal cancer models

Maione, Federica;Oddo, Daniele;Galvagno, Federica;Macagno, Marco;Barault, Ludovic;Gigliotti, Chiara;Mira, Alessia;Corti, Giorgio;Lamba, Simona;Riganti, Chiara;Castella, Barbara;Massaia, Massimo;Bardelli, Alberto;Di Nicolantonio, Federica
2024-01-01

Abstract

Serine/threonine-protein kinase B-raf (BRAF) mutations are found in 8-15% of colorectal cancer patients and identify a subset of tumors with poor outcome in the metastatic setting. We have previously reported that BRAF-mutant human cells display a high rate of protein production, causing proteotoxic stress, and are selectively sensitive to the proteasome inhibitors bortezomib and carfilzomib. In this work, we tested whether carfilzomib could restrain the growth of BRAF-mutant colorectal tumors not only by targeting cancer cells directly, but also by promoting an immune-mediated antitumor response. In human and mouse colorectal cancer cells, carfilzomib triggered robust endoplasmic reticulum stress and autophagy, followed by the emission of immunogenic-damage-associated molecules. Intravenous administration of carfilzomib delayed the growth of BRAF-mutant murine tumors and mobilized the danger-signal proteins calreticulin and high mobility group box 1 (HMGB1). Analyses of drug-treated samples revealed increased intratumor recruitment of activated cytotoxic T cells and natural killers, concomitant with the downregulation of forkhead box protein P3 (Foxp3)(+) T-cell surface glycoprotein CD4 (CD4)T+ cells, indicating that carfilzomib promotes reshaping of the immune microenvironment of BRAF-mutant murine colorectal tumors. These results will inform the design of clinical trials in BRAF-mutant colorectal cancer patients.
2024
1
19
BRAF mutant colorectal cancer; endoplasmic reticulum stress; immune microenvironment; immunogenic cell death; oncogene; proteasome inhibitors
Maione, Federica; Oddo, Daniele; Galvagno, Federica; Falcomatà, Chiara; Pandini, Marta; Macagno, Marco; Pessei, Valeria; Barault, Ludovic; Gigliotti, ...espandi
File in questo prodotto:
File Dimensione Formato  
Maione, Mol Oncol MS 2024.pdf

Accesso aperto

Descrizione: Maione Mol Oncol 2024
Tipo di file: PDF EDITORIALE
Dimensione 5.58 MB
Formato Adobe PDF
5.58 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1965218
Citazioni
  • ???jsp.display-item.citation.pmc??? 0
  • Scopus 0
  • ???jsp.display-item.citation.isi??? 0
social impact