LKB1-SIK2 loss drives uveal melanoma proliferation and hypersensitivity to SLC8A1 and ROS inhibition.
Sarah ProteauImène KrossaChrystel HusserMaxime GuéguinouFederica SellaKarine BilleMarie IrondelleMélanie DalmassoThibault BarouilletYann CheliCéline PisibonNicole ArrighiSacha Nahon-EstèveArnaud MartelLauris GastaudSandra LassalleOlivier MignenPatrick BrestNathalie M MazureFrédéric BostStéphanie BaillifSolange LandrevilleSimon TurcotteDan HassonSaul CarcamoChristophe VandierEmily BernsteinLaurent Yvan-CharvetMitchell Paul LevesqueRobert BallottiCorine BertolottoThomas StrubPublished in: EMBO molecular medicine (2023)
Metastatic uveal melanomas are highly resistant to all existing treatments. To address this critical issue, we performed a kinome-wide CRISPR-Cas9 knockout screen, which revealed the LKB1-SIK2 module in restraining uveal melanoma tumorigenesis. Functionally, LKB1 loss enhances proliferation and survival through SIK2 inhibition and upregulation of the sodium/calcium (Na + /Ca 2+ ) exchanger SLC8A1. This signaling cascade promotes increased levels of intracellular calcium and mitochondrial reactive oxygen species, two hallmarks of cancer. We further demonstrate that combination of an SLC8A1 inhibitor and a mitochondria-targeted antioxidant promotes enhanced cell death efficacy in LKB1- and SIK2-negative uveal melanoma cells compared to control cells. Our study also identified an LKB1-loss gene signature for the survival prognostic of patients with uveal melanoma that may be also predictive of response to the therapy combination. Our data thus identify not only metabolic vulnerabilities but also new prognostic markers, thereby providing a therapeutic strategy for particular subtypes of metastatic uveal melanoma.
Keyphrases
- reactive oxygen species
- cell death
- crispr cas
- cell cycle arrest
- signaling pathway
- squamous cell carcinoma
- small cell lung cancer
- skin cancer
- oxidative stress
- induced apoptosis
- papillary thyroid
- genome editing
- cell proliferation
- stem cells
- basal cell carcinoma
- genome wide
- cancer therapy
- copy number
- endoplasmic reticulum stress
- transcription factor
- data analysis
- artificial intelligence
- dna methylation
- lymph node metastasis
- squamous cell
- cell therapy