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.

Effect of White Potatoes on Subjective Appetite, Food Intake, and Glycemic Response in Healthy Older Adults.

The objective of this study was to determine the effect of white potato cooking methods on subjective appetite, short-term food intake (FI), and glycemic response in healthy older adults. Using a within-subject, repeated-measures design, 20 participants (age: 70.4 ± 0.6 y) completed, in random order, five treatment conditions: three potato treatments (baked potatoes, mashed potatoes, and French fries), an isocaloric control treatment (white bread), or a fasting condition (meal skipping). Subjective appetite and glycemic response were measured for 120 min using visual analogue scales and capillary blood samples, respectively. Lunch FI was measured with an ad libitum pizza meal at 120 min. Change from baseline subjective appetite (p < 0.001) and lunch FI (p < 0.001) were lower after all test treatments compared with meal skipping (p < 0.001), but did not differ among test treatments. Cumulative FI (test treatment + lunch FI) did not differ among treatment conditions. Blood glucose concentrations were higher after all test treatments compared with meal skipping (p < 0.001), but were not different from each other. In healthy older adults, white potatoes suppressed subjective appetite and lunch FI compared with meal skipping, suggesting white potatoes do not bypass regulatory control mechanisms of FI.