Characterization of dabrafenib-induced drug insensitivity via cellular barcoding and collateral sensitivity to second-line therapeutics.

Journal

Scientific reports

ISSN: 2045-2322

Titre abrégé: Sci Rep

Pays: England

ID NLM: 101563288

Informations de publication

Date de publication:
02 Jan 2024

Historique:

received: 14 05 2023

accepted: 20 12 2023

medline: 4 1 2024

pubmed: 4 1 2024

entrez: 3 1 2024

Statut: epublish

Résumé

Drug insensitivity is arguably one of the biggest challenges in cancer therapeutics. Although effective therapeutic solutions in cancer are limited due to the emergence of drug insensitivity, exploiting evolutionary understanding in this context can provide potential second-line therapeutics sensitizing the drug insensitive populations. Targeted therapeutic agent dabrafenib is used to treat CRC patients with BRAF V600E genotype and insensitivity to dabrafenib is often observed. Understanding underlying clonal architecture of dabrafenib-induced drug insensitivity and identification of potential second-line therapeutics that could sensitize dabrafenib insensitive populations remain to be elucidated. For this purpose, we utilized cellular barcoding technology to decipher dabrafenib-induced clonal evolution in BRAF V600E mutant HT-29 cells. This approach revealed the detection of both pre-existing and de novo barcodes with increased frequencies as a result of dabrafenib insensitivity. Furthermore, our longitudinal monitoring of drug insensitivity based on barcode detection from floating DNA within used medium enabled to identify temporal dynamics of pre-existing and de novo barcodes in relation to dabrafenib insensitivity in HT-29 cells. Moreover, whole-exome sequencing analysis exhibited possible somatic CNVs and SNVs contributing to dabrafenib insensitivity in HT-29 cells. Last, collateral drug sensitivity testing demonstrated oxaliplatin and capecitabine, alone or in combination, as successful second-like therapeutics in inducing collateral sensitivity in dabrafenib-insensitive HT-29 cells. Overall, our findings demonstrate clonal dynamics of dabrafenib-insensitivity in HT-29 cells. In addition, oxaliplatin and capecitabine, alone or in combination, were successful second-line therapeutics in inducing collateral sensitivity in dabrafenib-insensitive HT-29 cells.

Identifiants

DOI: 10.1038/s41598-023-50443-3 PMID: 38167959

pubmed: 38167959

doi: 10.1038/s41598-023-50443-3

pii: 10.1038/s41598-023-50443-3

doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Pagination

286

Subventions

Organisme : Türkiye Bilimsel ve Teknolojik Araştırma Kurumu

ID : 118C197

Informations de copyright

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