American Association for Cancer Research
15357163mct181385-sup-214077_5_supp_5942845_q22z52.pdf (355.14 kB)

Figure S1, Table S1, Table S2 from KLF4 p.A472D Mutation Contributes to Acquired Resistance to Cetuximab in Colorectal Cancer

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journal contribution
posted on 2023-04-03, 15:30 authored by Song Ye, Xiaoge Hu, Chao Ni, Weiwei Jin, Yaping Xu, Lianpeng Chang, Huaixiang Zhou, Jiahong Jiang, Liu Yang

Figure S1, Table S1, Table S2


Zhejiang University School of Medicine

Science Technology Department of Zhejiang Province


National Natural Science Foundation of China

project of Health Bureau of Zhejiang Province

Natural Science Foundation of Zhejiang Province



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.