Abstract 1322
Background
Monoclonal antibodies against the Epidermal Growth Factor Receptor (EGFR) such as cetuximab or panitumumab are used for the treatment of metastatic colorectal cancer (mCRC) patients. Unfortunately, most patients develop resistance against these therapies within months. Several studies have shown that aberrations in the RAS pathway are responsible for resistance. However, even in metastases that are refractory to anti-EGFR treatment a significant fraction of RAS wild-type (wt) cells remain. These findings suggest a cross-talk between RAS mutant and wt cells in mediating resistance in the wt compartment.
Methods
We used mouse and patient-derived organoids from mCRC as well as CRC cell lines to test the contribution of extracellular vesicles in mediating resistance in RAS wt cells. Using conditioned media, transfection experiments and liquid biopsies (plasma and urine) from patients differential expression of the let-7g microRNA was demonstrated in microvesicles from cetuximab sensitive and resistant cells. Changes in expression of the let-7g microRNA were further analysed by in-situ hybridization in tissues.
Results
Basal let-7g expression from pre-treatment plasma and urine samples of RAS wt patients correlated with clinical outcome and changes in let-7g circulating levels mirrored clinical behaviour. In-situ hybridization in tissues confirmed changes in expression of the let-7g microRNA observed in plasma and urine samples.
Conclusions
Our data suggest that let-7g microRNA might function as a paracrine mediator of anti-EGFR resistance and might be exploited as a non-invasive biomarker of resistance to cetuximab treatment. Further work is ongoing to characterize the molecular mechanisms underpinning let-7g mediated effect on anti-EGFR sensitivity in RAS wt CRC cells.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
N. Valeri: Speaker Bureau / Expert testimony: Bayer; Speaker Bureau / Expert testimony: Eli Lilly; Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Merck. All other authors have declared no conflicts of interest.
Resources from the same session
5678 - Nanomaterials Augmented LDI-TOF-MS for Hepatocellular Carcinoma Diagnosis and Classification
Presenter: Jian Zhou
Session: Poster Display session 3
Resources:
Abstract
2436 - Development and Validation of an RNA-Seq Assay for Gene Fusions Detection in Formalin-Fixed Paraffin-Embedded Samples
Presenter: Hua Dong
Session: Poster Display session 3
Resources:
Abstract
5271 - A Pilot Study to Implement an Artificial Intelligence (AI) System for Gastrointestinal Cancer Clinical Trial Matching
Presenter: Zhaohui Jin
Session: Poster Display session 3
Resources:
Abstract
4787 - A Blinded Comparison of Patient Treatments to Therapeutic Options Presented by an Artificial Intelligence-based Clinical Decision-support system
Presenter: Suthida Suwanvecho
Session: Poster Display session 3
Resources:
Abstract
5744 - OncOS: scalable and accurate next-generation sequencing analytics for precision oncology and personalized patient care
Presenter: Joe Thompson
Session: Poster Display session 3
Resources:
Abstract
3752 - The association between wearable device physical activity metrics and performance status in oncology: a systematic review
Presenter: Milan Kos
Session: Poster Display session 3
Resources:
Abstract
5820 - SomaticNET: neural network evaluation of somatic mutations in cancer
Presenter: Geoffroy Dubourg-Felonneau
Session: Poster Display session 3
Resources:
Abstract
4771 - Is there a role for Next-generation sequencing (NGS) profiling on metastatic non-colorectal gastrointestinal carcinomas (MNCGIC) in developing countries? A single center experience.
Presenter: Mauricio Ribeiro
Session: Poster Display session 3
Resources:
Abstract
1209 - Metastatic Cancer Whole-Exome Sequencing in daily practice
Presenter: Manon Réda
Session: Poster Display session 3
Resources:
Abstract
5702 - Genomic-Guided Individualized Precision Therapy in Refractory Metastatic Solid Tumor Patients with Extensively Poor Performance Status: A Chinese single institutional prospective observational real-world study
Presenter: Haitao Wang
Session: Poster Display session 3
Resources:
Abstract