With the increase of treatment course, resistance to epidermal growth factor receptor (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 mCRC patients 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 CRC tissue-based datasets and one ctDNA dataset. The prevalence of mutations identified in ctDNA was consistent with both CRC tissue-... More
With the increase of treatment course, resistance to epidermal growth factor receptor (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 mCRC patients 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 CRC tissue-based datasets and one ctDNA dataset. The prevalence of mutations identified in ctDNA was consistent with both CRC 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 co-existed 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 CRC cells, which was associated with the increased phosphorylation of downstream EGFR signaling proteins. These results suggest that the KLF4 p.A472D may contribute to cetuximab resistance in patients with mCRC and thus, it may serve as a new biomarker in clinical application. Monitoring somatic mutations related to cetuximab resistance in mCRC patients through ctDNA may provide real-time insights for clinical reference and treatment planning.,Copyright ©2020, American Association for Cancer Research.
