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Honokiol enhances the sensitivity of cetuximab in KRAS G13D mutant colorectal cancer through destroying SNX3-retromer complex.
- Source :
-
Theranostics [Theranostics] 2024 Aug 26; Vol. 14 (14), pp. 5443-5460. Date of Electronic Publication: 2024 Aug 26 (Print Publication: 2024). - Publication Year :
- 2024
-
Abstract
- Rationale : the proto-oncogene KRAS is frequently mutated in colorectal cancer (CRC), leading to inherent resistance against monoclonal antibodies targeting the epidermal growth factor receptor (EGFR), such as cetuximab. Therefore, addressing the primary resistance and expanding the indications for target therapy have become critical challenges. Methods : the screening of a natural product library against KRAS mutant CRC cells was conducted, leading to the discovery of a small molecule compound that sensitive to the KRAS <superscript>G13D</superscript> mutation site. The anti-tumor activity of this small molecule compound in combination with cetuximab was evaluated using the KRAS <superscript>G13D</superscript> mutant CRC models both in vivo and in vitro . This evaluation includes an examination of its effects on cell proliferation, viability, apoptosis, cell cycle progression, and tumor growth. Furthermore, RNA sequencing, western blot analysis, immunofluorescence, real-time quantitative PCR, and pull-down assays were employed to explore the molecular mechanisms underlying the synergistic anti-tumor effect of this small molecule compound in combination with cetuximab. Results : our study screened 882 compounds in KRAS mutant CRC cells and identified honokiol, a small molecule compound that exhibits specific sensitivity to KRAS <superscript>G13D</superscript> mutant CRC cells. Furthermore, we revealed that the synergistic augmentation of cetuximab's sensitivity in vivo and in vitro models of KRAS <superscript>G13D</superscript> mutant CRC in combination with honokiol. Mechanistically, honokiol suppresses SNX3-retromer mediated trafficking, thereby impeding lysosomal proteolytic capacity and inhibiting autophagy and macropinocytosis fluxes. Moreover, honokiol inhibits the conversion of RAS GDP to RAS GTP, heightening the susceptibility of KRAS <superscript>G13D</superscript> CRC mutant cells to cetuximab. Conclusions : honokiol enhances the sensitivity of cetuximab by destroying SNX3 retromer in KRAS <superscript>G13D</superscript> mutant CRC preclinical model. These findings present a promising strategy for expanding the indications of target therapy in KRAS mutant colorectal cancer patients.<br />Competing Interests: Competing Interests: The authors have declared that no competing interest exists.<br /> (© The author(s).)
- Subjects :
- Humans
Animals
Cell Line, Tumor
Mice
Xenograft Model Antitumor Assays
Proto-Oncogene Mas
Drug Synergism
Mice, Nude
Drug Resistance, Neoplasm drug effects
Drug Resistance, Neoplasm genetics
Mice, Inbred BALB C
Allyl Compounds
Phenols
Cetuximab pharmacology
Cetuximab therapeutic use
Colorectal Neoplasms drug therapy
Colorectal Neoplasms genetics
Colorectal Neoplasms pathology
Colorectal Neoplasms metabolism
Proto-Oncogene Proteins p21(ras) genetics
Proto-Oncogene Proteins p21(ras) metabolism
Lignans pharmacology
Lignans therapeutic use
Biphenyl Compounds pharmacology
Biphenyl Compounds therapeutic use
Mutation
Cell Proliferation drug effects
Apoptosis drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1838-7640
- Volume :
- 14
- Issue :
- 14
- Database :
- MEDLINE
- Journal :
- Theranostics
- Publication Type :
- Academic Journal
- Accession number :
- 39310106
- Full Text :
- https://doi.org/10.7150/thno.97180