Data from Therapeutic Targeting of DGKA-Mediated Macropinocytosis Leads to Phospholipid Reprogramming in Tuberous Sclerosis Complex

• DOI: 10.1158/0008-5472.c.6513499.v1
• Publication Date: 2023-03-31T09:46:03Z
• Authors: Andrii Kovalenko; Andres Sanin; Kosmas Kosmas; Long Zhang; Ji Wang; Elie W. Akl; Krinio Giannikou; Clemens K. Probst; Thomas R. Hougard; Ryan W. Rue; Vera P. Krymskaya; John M. Asara; Hilaire C. Lam; David J. Kwiatkowski; Elizabeth P. Henske; Harilaos Filippakis
• Keywords: Ritanserin; TSC2; TSC1; Lymphangioleiomyomatosis

<div>Abstract<p>Lymphangioleiomyomatosis is a rare destructive lung disease affecting primarily women and the primary manifestation of tuberous sclerosis complex (TSC). In lymphangioleiomyomatosis, biallelic loss TSC1/2 leads to hyperactivation mTORC1 inhibition autophagy. To determine how metabolic vulnerabilities TSC2-deficient cells can be targeted, we performed high-throughput screen utilizing “Repurposing” library at Broad Institute MIT Harvard (Cambridge, MA), with or without autophagy inhibitor chloroquine. Ritanserin, an diacylglycerol kinase alpha (DGKA), was identified as selective proliferation Tsc2<sup>−/−</sup> mouse embryonic fibroblasts (MEF), no impact on Tsc2<sup>+/+</sup> MEFs. DGKA lipid that metabolizes phosphatidic acid, key component plasma membranes. Phosphatidic acid levels were increased 5-fold in MEFs compared MEFs, treatment ritanserin led depletion well rewiring phospholipid metabolism. Macropinocytosis known upregulated cells. Ritanserin decreased macropinocytic uptake albumin, limited number lysosomes, reduced lysosomal activity model TSC, cyst frequency volume, genetic downregulation prevented alveolar destruction airspace enlargement. Collectively, these data indicate supports macropinocytosis maintain homeostasis promote proliferation. Targeting may represent novel therapeutic approach for TSC lymphangioleiomyomatosis.</p>Significance:<p>This study identifies metabolism mechanisms mTORC1-hyperactive suggest strategy use tumors, including pancreatic cancer.</p></div>