Understanding cancer drug resistance with Sleeping Beauty functional genomic screens: Application to MAPK inhibition in cutaneous melanoma

Eliot Y Zhu; Jacob L Schillo; Sarina D Murray; Jesse D Riordan; Adam J Dupuy

doi:10.1016/j.isci.2023.107805

Understanding cancer drug resistance with Sleeping Beauty functional genomic screens: Application to MAPK inhibition in cutaneous melanoma

iScience. 2023 Aug 31;26(10):107805. doi: 10.1016/j.isci.2023.107805. eCollection 2023 Oct 20.

Authors

Eliot Y Zhu^{1

2}, Jacob L Schillo^{1

2}, Sarina D Murray^{1

2}, Jesse D Riordan^{1

2}, Adam J Dupuy^{1

2}

Affiliations

¹ Department of Anatomy and Cell Biology, Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA.
² Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA.

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, RAC1^P29S. 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.

Keywords: Cancer; Chemosensitivity; Genomics; Molecular medicine.

Abstract

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