E-MTAB-8595
Gain-of-function CRISPR screens identify tumor driver genes conferring melanoma cell plasticity and therapy-resistance
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.
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.