Cetuximab Enhanced the Cytotoxic Activity of Immune Cells during Treatment of Colorectal Cancer

Wang, Lin; Wei, Yu; Fang, Weijia; Lu, Chong; Chen, Jianing; Cui, Guangying; Diao, Hongyan

doi:10.1159/000485404

Cited by 36 publications

(24 citation statements)

References 39 publications

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“…Earlier reports described IC 50 values for cetuximab in the millimolar range, either directly measured or extrapolated [9, 26, 27], while biologically relevant concentrations were reported to be in the nanomolar range [28]. In addition to preventing the binding of ligand to its receptor, cetuximab exerts antibody-derived cellular cytotoxicity, not recapitulated well under cell culture conditions [29, 30].…”

Section: Resultsmentioning

confidence: 99%

Heterogeneous pathway activation and drug response modelled in colorectal-tumor-derived 3D cultures

et al. 2019

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Organoid cultures derived from colorectal cancer (CRC) samples are increasingly used as preclinical models for studying tumor biology and the effects of targeted therapies under conditions capturing in vitro the genetic make-up of heterogeneous and even individual neoplasms. While 3D cultures are initiated from surgical specimens comprising multiple cell populations, the impact of tumor heterogeneity on drug effects in organoid cultures has not been addressed systematically. Here we have used a cohort of well-characterized CRC organoids to study the influence of tumor heterogeneity on the activity of the KRAS/MAPK-signaling pathway and the consequences of treatment by inhibitors targeting EGFR and downstream effectors. MAPK signaling, analyzed by targeted proteomics, shows unexpected heterogeneity irrespective of RAS mutations and is associated with variable responses to EGFR inhibition. In addition, we obtained evidence for intratumoral heterogeneity in drug response among parallel “sibling” 3D cultures established from a single KRAS -mutant CRC. Our results imply that separate testing of drug effects in multiple subpopulations may help to elucidate molecular correlates of tumor heterogeneity and to improve therapy response prediction in patients.

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Section: Resultsmentioning

confidence: 99%

Heterogeneous pathway activation and drug response modelled in colorectal-tumor-derived 3D cultures

et al. 2019

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“…Cetuximab-EGFR complex formation inhibits proliferation and enhances apoptosis, as well as reduces angiogenesis, invasiveness and metastasis in tumours[ 99 ]. Also, cetuximab induces antibody-dependent cellular cytotoxicity (ADCC)[ 100 ] through NK and CD8+ T cells[ 101 ]. Cetuximab is approved by FDA[ 102 ] and EMA[ 103 ] as Erbitux ® for the treatment of K-ras wild-type, EGFR-expressing metastatic colorectal cancer and for squamous cell carcinoma of the head and neck (SCCHN).…”

Section: Clinical Implications Of Molecular Gc Classification: Impactmentioning

confidence: 99%

New therapeutic options opened by the molecular classification of gastric cancer

Chivu‐Economescu¹,

Matei²,

Necula³

et al. 2018

WJG

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Gastric cancer (GC) is one of the most lethal and aggressive cancers, being the third cause of cancer related death worldwide. Even with radical gastrectomy and the latest generation of molecular chemotherapeutics, the numbers of recurrence and mortality remains high. This is due to its biological heterogeneity based on the interaction between multiple factors, from genomic to environmental factors, diet or infections with various pathogens. Therefore, understanding the molecular characteristics at a genomic level is critical to develop new treatment strategies. Recent advances in GC molecular classification provide the unique opportunity to improve GC therapy by exploiting the biomarkers and developing novel targeted therapy specific to each subtype. This article highlights the molecular characteristics of each subtype of gastric cancer that could be considered in shaping a therapeutic decision, and also presents the completed and ongoing clinical trials addressed to those targets. The implementation of the novel molecular classification system will allow a preliminary patient selection for clinical trials, a mandatory issue if it is desired to test the efficacy of a certain inhibitor to the given target. This will represent a substantial advance as well as a powerful tool for targeted therapy. Nevertheless, translating the scientific results into new personalized treatment opportunities is needed in order to improve clinical care, the survival and quality of life of patients with GC.

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“…In addition to the factors of KRAS alleles itself, NRF2 is also involved in the resistance mechanism in KRAS G12D mutant pancreatic cancer [19]. As cetuximab has been reported to have some immune influence in CRC patients by increasing the number of CD3+ T, CD8+ T and natural killer (NK) cells and reducing T-regulatory cells [20], we mapped 145 genes of interest to 1040 immune genes, and 10 immune genes were filtered out for subsequent studies about their association with treatment efficacy or drug resistance.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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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.

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Cetuximab Enhanced the Cytotoxic Activity of Immune Cells during Treatment of Colorectal Cancer

Cited by 36 publications

References 39 publications

Heterogeneous pathway activation and drug response modelled in colorectal-tumor-derived 3D cultures

Heterogeneous pathway activation and drug response modelled in colorectal-tumor-derived 3D cultures

New therapeutic options opened by the molecular classification of gastric cancer

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

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