Preclinical efficacy of carfilzomib in BRAF‐mutant colorectal cancer models

• DOI: 10.1002/1878-0261.13595
• Publication Date: 2024-02-13T09:32:11Z
• Authors: Federica Maione; Daniele Oddo; Federica Galvagno; Chiara Falcomatà; Marta Pandini; Marco Macagno; Valeria Pessei; Ludovic Barault; Chiara Gigliotti; Alessia Mira; Giorgio Corti; Simona Lamba; Chiara Riganti; Barbara Castella; Massimo Massaia; Roland Rad; Dieter Saur; Alberto Bardelli; Federica Di Nicol...
• Keywords: Immunogenic cell death

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