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Gain-of-function CRISPR screens identify tumor driver genes conferring melanoma cell plasticity and therapy-resistance

ABSTRACT: Gain-of-function CRISPR screens identify tumor driver genes conferring melanoma cell plasticity and therapy-resistance

PROVIDER: PRJEB35800 | ENA |

REPOSITORIES: ENA

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Gain-of-function CRISPR screens identify tumor driver genes conferring melanoma cell plasticity and therapy-resistance

Project description:Most genetic events that drive melanoma development and resistance to targeted therapy have been uncovered. In contrast, and despite their increasingly recognized contribution, little is known about the non-genetic mechanisms that drive these processes. Here, we performed in vivo gain-of-function CRISPR screens and identified SMAD3, BIRC3 and SLC9A5 as key drivers of BRAFi-resistance and the tumor growth capability of persister cells. We show that their expression levels increase during acquisition of BRAFi-resistance, and remain high in persister cells and during relapse. Critically, chemical inhibition of SMAD3 or BIRC3 efficiently abrogates melanoma tumor growth and persister cells proliferation. Genetic inhibition of these targets efficiently restored the sensitivity of persister cells to BRAFi. Our work expands our understanding of the biology of persister cells and highlight novel drug vulnerabilities that can be exploited to develop long-lasting anti-melanoma therapies.

2021-02-03 | E-MTAB-8595 | biostudies-arrayexpress

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Project description:Most genetic alterations that drive melanoma development and resistance to targeted therapy have been uncovered. In contrast, and despite their increasingly recognized contribution, little is known about the non-genetic mechanisms that drive these processes. Here, we performed in vivo gain-of-function CRISPR screens and identified SMAD3, BIRC3, and SLC9A5 as key actors of BRAFi resistance. We show that their expression levels increase during acquisition of BRAFi resistance and remain high in persister cells and during relapse. The upregulation of the SMAD3 transcriptional activity (SMAD3-signature) promotes a mesenchymal-like phenotype and BRAFi resistance by acting as an upstream transcriptional regulator of potent BRAFi-resistance genes such as EGFR and AXL. This SMAD3-signature predicts resistance to both current melanoma therapies in different cohorts. Critically, chemical inhibition of SMAD3 may constitute amenable target for melanoma since it efficiently abrogates persister cells survival. Interestingly, decrease of SMAD3 activity can also be reached by inhibiting the Aryl hydrocarbon Receptor (AhR), another druggable transcription factor governing SMAD3 expression level. Our work highlights novel drug vulnerabilities that can be exploited to develop long-lasting antimelanoma therapies.

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