Abstract:
:With the increase of treatment course, resistance to EGFR blockade is inevitable in patients with metastatic colorectal cancer (mCRC). KRAS mutations have been considered to be primary drivers of this resistance; however, the potential function of other genes has not been extensively investigated. This study collected 17 plasma samples from patients with mCRC with cetuximab resistance, and target-capture deep sequencing was used to identify mutations in circulating tumor DNA (ctDNA). Analysis of mutational prevalence in ctDNA was performed from three colorectal cancer tissue-based datasets and one ctDNA dataset. The prevalence of mutations identified in ctDNA was consistent with both colorectal cancer tissue-based and ctDNA datasets. Clonal analysis revealed that 41.2% of patients were positive for at least one subclone. Multiple mechanisms of cetuximab resistance were coexisted in individual patients, and one of the patients even harbored nine distinct mutations. In particular, functional study of Krüppel-like factor 4 (KLF4) p.A472D revealed increased cetuximab resistance in colorectal cancer cells, which was associated with the increased phosphorylation of downstream EGFR signaling proteins. These results suggest that KLF4 p.A472D may contribute to cetuximab resistance in patients with mCRC and thus may serve as a new biomarker in clinical application. Monitoring somatic mutations related to cetuximab resistance in patients with mCRC through ctDNA may provide real-time insights for clinical reference and treatment planning.
journal_name
Mol Cancer Therjournal_title
Molecular cancer therapeuticsauthors
Ye S,Hu X,Ni C,Jin W,Xu Y,Chang L,Zhou H,Jiang J,Yang Ldoi
10.1158/1535-7163.MCT-18-1385subject
Has Abstractpub_date
2020-03-01 00:00:00pages
956-965issue
3eissn
1535-7163issn
1538-8514pii
1535-7163.MCT-18-1385journal_volume
19pub_type
杂志文章abstract::Clinical translation of intravenous therapies to treat disseminated or metastatic cancer is imperative. Comparative oncology, the evaluation of novel cancer therapies in animals with spontaneous cancer, can be utilized to inform and accelerate clinical translation. Preclinical murine studies demonstrate that single-sh...
journal_title:Molecular cancer therapeutics
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-04-0342
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journal_title:Molecular cancer therapeutics
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journal_title:Molecular cancer therapeutics
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pub_type: 杂志文章
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journal_title:Molecular cancer therapeutics
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更新日期:2021-01-01 00:00:00