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Loss-of-function mutation of REV1 (p.R704Q) mediates cetuximab primary resistance by activating autophagy in RAS-wild type metastatic colorectal cancer.
- Source :
-
Cancer letters [Cancer Lett] 2024 Aug 28; Vol. 598, pp. 217103. Date of Electronic Publication: 2024 Jul 04. - Publication Year :
- 2024
-
Abstract
- Cetuximab in combination with FOLFIRI/FOLFOX is the standard first-line treatment for patients with RAS wild-type metastatic colorectal cancer (mCRC). However, some patients experience rapid tumor progression after treatment with cetuximab (primary resistance). Our previous research identified a gene mutation, REV1 p.R704Q, which may be a key biomarker for primary cetuximab resistance. This study aimed to study the mechanism of cetuximab resistance caused by REV1 p.R704Q mutation and reveal a novel mechanism to induce cetuximab resistance. Sanger sequencing and multivariate clinical prognostic analysis of 208 patients with mCRC showed that REV1 p.R704Q mutation is an independent risk factor for tumor progression after treatment with cetuximab in patients with RAS wild-type mCRC (Hazard ratio = 2.481, 95 % Confidence interval: 1.389-4.431, P = 0.002). The sensitivity of REV1 p.R704Q mutant cell lines to cetuximab decreased in vitro Cell Counting Kit-8 assay and in vivo subcutaneous tumor model. In vitro, we observed that decreased stability and accelerated degradation of REV1 mutant protein results in REV1 dysfunction, which activated autophagy and mediated cetuximab resistance. These findings suggested that REV1 p.R704Q mutation could predict cetuximab primary resistance in mCRC. REV1 p.R704Q mutation caused decreased stability and degradation of REV1 protein, as well as dysfunction of p.R704Q protein. REV1 p.R704Q mutation activates autophagy and mediates cetuximab resistance; further, inhibition of autophagy could reverse cetuximab resistance.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
- Subjects :
- Humans
Male
Female
Animals
Mice
Middle Aged
Cell Line, Tumor
Xenograft Model Antitumor Assays
Aged
Antineoplastic Agents, Immunological pharmacology
Antineoplastic Agents, Immunological therapeutic use
Mice, Nude
Prognosis
Cetuximab pharmacology
Colorectal Neoplasms genetics
Colorectal Neoplasms drug therapy
Colorectal Neoplasms pathology
Drug Resistance, Neoplasm genetics
Autophagy drug effects
Autophagy genetics
Mutation
Subjects
Details
- Language :
- English
- ISSN :
- 1872-7980
- Volume :
- 598
- Database :
- MEDLINE
- Journal :
- Cancer letters
- Publication Type :
- Academic Journal
- Accession number :
- 38969162
- Full Text :
- https://doi.org/10.1016/j.canlet.2024.217103