Dynamic alterations of genome and transcriptome in KRAS G13D mutant CRC PDX model treated with cetuximab

Hangyu Zhang,Zhou Tong,Cong Yan,Yi Zheng,Peng Zhao,Qihan Fu,Weijia Fang,Weiqin Jiang,Lulu Liu,Jinming Cheng,Guoqing Zhang,Liyun Yuan

doi:10.1186/s12885-020-06909-y

Abstract

BackgroundKRAS mutations have been characterized as the major predictive biomarkers for resistance to cetuximab treatment. However, studies indicate that not all KRAS mutations are associated with equivalent treatment outcomes. KRAS G13D mutations were observed to account for approximately 16% of all KRAS mutations in advanced colorectal cancer patients, and whether these patients can benefit from cetuximab has not been determined.MethodsAn established KRAS G13D mutant colorectal cancer (CRC) patient-derived xenograft (PDX) model was treated with cetuximab. After repeated use of cetuximab, treatment-resistant PDX models were established. Tissue samples were collected before and during treatment, and multiomics data were subsequently sequenced and processed, including whole-exome, mRNA and miRNA data, to explore potential dynamic changes.ResultsCetuximab treatment initially slowed tumor growth, but resistance developed not long after treatment. WES (whole-exome sequencing) and RNA sequencing found that 145 genes had low P values (< 0.01) when analyzed between the locus genotype and its related gene expression level. Among these genes, SWAP70 was believed to be a probable cause of acquired resistance. JAK2, PRKAA1, FGFR2 and RALBP1, as well as 10 filtered immune-related genes, also exhibited dynamic changes during the treatment.ConclusionsCetuximab may be effective in KRAS G13D mutation patients. Dynamic changes in transcription, as determined by WES and RNA sequencing, occurred after repeated drug exposure, and these changes were believed to be the most likely cause of drug resistance.

Highlights

KRAS mutations have been characterized as the major predictive biomarkers for resistance to cetuximab treatment
In this study, the cetuximab-resistant KRAS G13D mutation Colorectal cancer (CRC) patient-derived xenograft (PDX) model was induced by repeated use of cetuximab, and the therapeutic efficacy and genomic and transcriptome changes of tumors were dynamically observed in each generation of mice during the treatment process to find the potential drug resistance mechanism
When the tumors reached 100–300 mm3, the mice were randomly segregated into two groups for treatment, with 3 mice with similar average tumor volume being included in each group, and the established PDX model was passage 1 (P1)

Summary

Introduction

KRAS mutations have been characterized as the major predictive biomarkers for resistance to cetuximab treatment. Compared to other cancer types, there are relatively few drugs available for CRC patients. Previous studies demonstrated that mutations in KRAS were major predictive biomarkers for resistance to treatment with cetuximab, which is an anti-epidermal growth factor receptor (EGFR) monoclonal antibody (MoAb). The duration of response to antiEGFR therapy in KRAS wild-type patients is relatively short, and most patients become refractory within 3–12 months [2], even those whose treatments are initially highly effective. Based on these findings, primary and secondary resistance to cetuximab have been thoroughly studied

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Results

Conclusion