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Negative correlation between acetyl-CoA acyltransferase 2 and cetuximab resistance in colorectal cancer
Yitao Yuan1, Xun Sun1, Mengling Liu1
1Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
Abstract:
The emergence of anti-EGFR therapy has revolutionized the treatment of colorectal cancer (CRC). However, not all patients respond consistently well. Therefore, it is imperative to conduct further research to identify the molecular mechanisms underlying the development of cetuximab resistance in CRC. In this study, we find that the expressions of many metabolism-related genes are downregulated in cetuximab-resistant CRC cells compared to their sensitive counterparts. Specifically, acetyl-CoA acyltransferase 2 (ACAA2), a key enzyme in fatty acid metabolism, is downregulated during the development of cetuximab resistance. Silencing of ACAA2 promotes proliferation and increases cetuximab tolerance in CRC cells, while overexpression of ACAA2 exerts the opposite effect. RTK-Kras signaling might contribute to the downregulation of ACAA2 expression in CRC, and ACAA2 predicts CRC prognosis in patients with Kras mutations. Collectively, our data suggest that modulating ACAA2 expression contributes to secondary cetuximab resistance in Kras wild-type CRC patients. ACAA2 expression is related to Kras mutation and demonstrates a prognostic role in CRC patients with Kras mutation. Thus, ACAA2 is a potential target in CRC with Kras mutation.
Insights
Acetyl-CoA acyltransferase 2 (ACAA2) downregulation promotes cetuximab resistance in colorectal cancer (CRC). Restoring ACAA2 expression may offer a new therapeutic strategy for CRC patients with Kras mutations.
Area of Science:
- Molecular Oncology
- Cancer Metabolism
- Colorectal Cancer Therapeutics
Background:
- Anti-EGFR therapy, including cetuximab, has transformed colorectal cancer (CRC) treatment.
- Acquired resistance to cetuximab remains a significant clinical challenge, necessitating research into resistance mechanisms.
- Understanding molecular drivers of cetuximab resistance is crucial for improving patient outcomes.
Purpose of the Study:
- To investigate molecular mechanisms underlying cetuximab resistance in colorectal cancer (CRC).
- To identify key genes and pathways involved in the development of acquired resistance to anti-EGFR therapy.
- To evaluate the role of acetyl-CoA acyltransferase 2 (ACAA2) in cetuximab resistance and its prognostic significance in CRC.
Main Methods:
- Comparative analysis of gene expression profiles between cetuximab-sensitive and resistant CRC cells.
- Functional studies involving gene silencing and overexpression of ACAA2 in CRC cell lines.
- Investigation of the relationship between RTK-Kras signaling, ACAA2 expression, and patient prognosis.
Main Results:
- Downregulation of metabolism-related genes, including acetyl-CoA acyltransferase 2 (ACAA2), was observed in cetuximab-resistant CRC cells.
- Silencing ACAA2 enhanced CRC cell proliferation and cetuximab tolerance, while ACAA2 overexpression had the opposite effect.
- ACAA2 expression is linked to Kras mutation status and predicts prognosis in CRC patients with Kras mutations.
Conclusions:
- Modulating ACAA2 expression contributes to secondary cetuximab resistance in colorectal cancer.
- ACAA2 plays a critical role in regulating CRC cell response to anti-EGFR therapy.
- ACAA2 represents a potential therapeutic target for colorectal cancer, particularly in patients with Kras mutations.
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