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

Abstract

Background: KRAS 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. Methods: An 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. Results: Cetuximab 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. Conclusions: Cetuximab 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.

Patient-derived tumor models: a more suitable tool for pre-clinical studies in colorectal cancer

“…After repeated treatment tumor acquired resistance to cetuximab, and significant changes were identified in JAK2, PRKAA1, FGFR2, and RALBP1 expression. In particular, SWAP70 , related to tumor development, may be a probable gene involved in cetuximab resistance in KRAS G13D CRC [ 110 ].…”

Complete Response With Cetuximab-Based Treatment of Metastatic Colorectal Cancers: Two Case Reports and Literature Review

“…In the CRC first-line chemotherapy, anti-EGFR monoclonal antibodies have been clinically and statistically confirmed less effective when treating patients with RAS and BRAF mutations ( 7 , 8 , 28 , 29 ). However, quite a few studies supported that cetuximab might be effective in KRAS G13D mutation (accounts for approximate 16% of all KRAS mutations) ( 30 , 31 ). In terms of the microsatellite instability, a recent study implied that cetuximab could even promote disease progression in stage III colon cancer patients with deficient mismatch repairing ( 5 ).…”

Patient‐derived xenograft model in colorectal cancer basic and translational research

“… 120 A recent study reported the dynamic alterations of biomarkers in KRAS G13D mutant CRC PDX model treated with cetuximab. 121 The expression of EGFR ligands is associated with the sensitivity of CRC to cetuximab, and the gene copy number of some oncogenes ( BRAF , EGFR , and KRAS ) is correlated positively with cetuximab and erlotinib sensitivity. 120 , 122 The implementing systems and molecular images were established to predict the efficacy of BCL‐2 inhibition in CRC based on a PDX cohort.…”

“…Moreover, the downregulation in classical EGFR‐mediated signaling and the upregulation in antiapoptotic signaling are associated with acquired cetuximab resistance 120 . A recent study reported the dynamic alterations of biomarkers in KRAS G13D mutant CRC PDX model treated with cetuximab 121 . The expression of EGFR ligands is associated with the sensitivity of CRC to cetuximab, and the gene copy number of some oncogenes ( BRAF , EGFR , and KRAS ) is correlated positively with cetuximab and erlotinib sensitivity 120,122 .…”