Journal article
Understanding cancer drug resistance with Sleeping Beauty functional genomic screens: application to MAPK inhibition in cutaneous melanoma
iScience, Vol.26(10), 107805
10/2023
DOI: 10.1016/j.isci.2023.107805
PMCID: PMC10582486
PMID: 37860756
Abstract
Combined BRAF and MEK inhibition is an effective treatment for BRAF-mutant cutaneous melanoma. However, most patients progress on this treatment due to drug resistance. Here, we applied the Sleeping Beauty transposon system to understand how melanoma evades MAPK inhibition. We found that the specific drug resistance mechanisms differed across melanomas in our genetic screens of five cutaneous melanoma cell lines. While drivers that reactivated MAPK were highly conserved, many others were cell-line specific. One such driver, VAV1, activated a de-differentiated transcriptional program like that of hyperactive RAC1, RAC1P29S. To target this mechanism, we showed that an inhibitor of SRC, saracatinib, blunts the VAV1-induced transcriptional reprogramming. Overall, we highlighted the importance of accounting for melanoma heterogeneity in treating cutaneous melanoma with MAPK inhibitors. Moreover, we demonstrated the utility of the Sleeping Beauty transposon system in understanding cancer drug resistance.
Details
- Title: Subtitle
- Understanding cancer drug resistance with Sleeping Beauty functional genomic screens: application to MAPK inhibition in cutaneous melanoma
- Creators
- Eliot Y. ZhuSarina D. MurrayJesse D. RiordanAdam J. Dupuy
- Resource Type
- Journal article
- Publication Details
- iScience, Vol.26(10), 107805
- DOI
- 10.1016/j.isci.2023.107805
- PMID
- 37860756
- PMCID
- PMC10582486
- NLM abbreviation
- iScience
- ISSN
- 2589-0042
- eISSN
- 2589-0042
- Language
- English
- Electronic publication date
- 08/2023
- Date published
- 10/2023
- Academic Unit
- Anatomy and Cell Biology; Pathology
- Record Identifier
- 9984463128302771
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