Abstract:
:Functional lysosomes mediate autophagy and macropinocytosis for nutrient acquisition. Pancreatic ductal adenocarcinoma (PDAC) tumors exhibit high basal lysosomal activity, and inhibition of lysosome function suppresses PDAC cell proliferation and tumor growth. However, the codependencies induced by lysosomal inhibition in PDAC have not been systematically explored. We performed a comprehensive pharmacological inhibition screen of the protein kinome and found that replication stress response (RSR) inhibitors were synthetically lethal with chloroquine (CQ) in PDAC cells. CQ treatment reduced de novo nucleotide biosynthesis and induced replication stress. We found that CQ treatment caused mitochondrial dysfunction and depletion of aspartate, an essential precursor for de novo nucleotide synthesis, as an underlying mechanism. Supplementation with aspartate partially rescued the phenotypes induced by CQ. The synergy of CQ and the RSR inhibitor VE-822 was comprehensively validated in both 2D and 3D cultures of PDAC cell lines, a heterotypic spheroid culture with cancer-associated fibroblasts, and in vivo xenograft and syngeneic PDAC mouse models. These results indicate a codependency on functional lysosomes and RSR in PDAC and support the translational potential of the combination of CQ and RSR inhibitors.
journal_name
Proc Natl Acad Sci U S Aauthors
Elliott IA,Dann AM,Xu S,Kim SS,Abt ER,Kim W,Poddar S,Moore A,Zhou L,Williams JL,Capri JR,Ghukasyan R,Matsumura C,Tucker DA,Armstrong WR,Cabebe AE,Wu N,Li L,Le TM,Radu CG,Donahue TRdoi
10.1073/pnas.1812410116subject
Has Abstractpub_date
2019-04-02 00:00:00pages
6842-6847issue
14eissn
0027-8424issn
1091-6490pii
1812410116journal_volume
116pub_type
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