LKB1‐SIK2 loss drives uveal melanoma proliferation and hypersensitivity to SLC8A1 and ROS inhibition

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+/Ca2+) 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.

• Publication year

  2023

• Venue

  EMBO Molecular Medicine

• Publication date

  2023-11-15

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.15252/emmm.202317719PMID 37966164PMCID 10701601
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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