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LKB1-SIK2 loss drives uveal melanoma proliferation and hypersensitivity to SLC8A1 and ROS inhibition
Sarah Proteau1,2, Imène Krossa1,2, Chrystel Husser1,2
1University Côte d'Azur, Nice, France.
Abstract:
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.
Insights
Loss of LKB1-SIK2 signaling in metastatic uveal melanoma drives cancer growth by increasing intracellular calcium. Targeting SLC8A1 and mitochondria offers a new therapeutic strategy for this resistant cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Metastatic uveal melanoma is a deadly cancer with limited treatment options.
- Understanding the molecular mechanisms of uveal melanoma resistance is crucial for developing new therapies.
Purpose of the Study:
- To identify novel therapeutic targets and strategies for metastatic uveal melanoma.
- To elucidate the role of the LKB1-SIK2 signaling pathway in uveal melanoma tumorigenesis.
Main Methods:
- A kinome-wide CRISPR-Cas9 knockout screen was employed to identify key regulators of uveal melanoma.
- Functional assays assessed the impact of LKB1 and SIK2 on cell proliferation, survival, and calcium signaling.
- In vitro studies evaluated the efficacy of combined SLC8A1 inhibition and antioxidant therapy.
Main Results:
- LKB1 loss was found to promote uveal melanoma growth by inhibiting SIK2 and upregulating the sodium/calcium exchanger SLC8A1.
- This leads to increased intracellular calcium and mitochondrial reactive oxygen species, promoting cancer hallmarks.
- Combination therapy with an SLC8A1 inhibitor and a mitochondria-targeted antioxidant demonstrated enhanced cell death in LKB1- and SIK2-deficient cells.
- An LKB1-loss gene signature was identified as a prognostic marker for uveal melanoma patient survival and a potential predictor of treatment response.
Conclusions:
- The LKB1-SIK2 pathway is a critical regulator of uveal melanoma tumorigenesis.
- Targeting SLC8A1 and mitochondrial pathways presents a promising therapeutic strategy for specific uveal melanoma subtypes.
- The identified LKB1-loss gene signature may aid in patient stratification and personalized treatment approaches.
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