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: Proto-Oncogene Proteins B-raf; BRAF mutant colorectal cancer; immune microenvironment; BRAF mutant colorectal cancer; endoplasmic reticulum stress; immune microenvironment; immunogenic cell death; oncogene; proteasome inhibitors; proteasome inhibitors; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; Antineoplastic Agents; Endoplasmic Reticulum Stress; Mice, Inbred C57BL; Mice; oncogene; Cell Line, Tumor; immunogenic cell death; Mutation; endoplasmic reticulum stress; Autophagy; Animals; Humans; Colorectal Neoplasms; Oligopeptides; RC254-282; Research Articles

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.