title: SIK2 Restricts Autophagic Flux To Support Triple-Negative Breast Cancer Survival.
abstract: Triple-negative breast cancer (TNBC) is a highly heterogeneous disease with multiple, distinct molecular subtypes that exhibit unique transcriptional programs and clinical progression trajectories. Despite knowledge of the molecular heterogeneity of the disease, most patients are limited to generic, indiscriminate treatment options: cytotoxic chemotherapy, surgery, and radiation. To identify new intervention targets in TNBC, we used large-scale, loss-of-function screening to identify molecular vulnerabilities among different oncogenomic backgrounds. This strategy returned salt inducible kinase 2 (SIK2) as essential for TNBC survival. Genetic or pharmacological inhibition of SIK2 leads to increased autophagic flux in both normal-immortalized and tumor-derived cell lines. However, this activity causes cell death selectively in breast cancer cells and is biased toward the claudin-low subtype. Depletion of ATG5, which is essential for autophagic vesicle formation, rescued the loss of viability following SIK2 inhibition. Importantly, we find that SIK2 is essential for TNBC tumor growth in vivo Taken together, these findings indicate that claudin-low tumor cells rely on SIK2 to restrain maladaptive autophagic activation. Inhibition of SIK2 therefore presents itself as an intervention opportunity to reactivate this tumor suppressor mechanism.
authors.affiliation: Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.|Simmons Comprehensive Cancer Center, UT-Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Kimberly E
authors.initials: KE
authors.lastname: Maxfield
authors.affiliation: Simmons Comprehensive Cancer Center, UT-Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Macion
authors.affiliation: Early Discovery & Medicinal Chemistry, Arrien Pharmaceuticals, Salt Lake City, Utah, USA.
authors.forename: Hariprasad
authors.initials: H
authors.lastname: Vankayalapati
authors.affiliation: Simmons Comprehensive Cancer Center, UT-Southwestern Medical Center, Dallas, Texas, USA angelique.whitehurst@utsouthwestern.edu.
authors.forename: Angelique W
authors.initials: AW
authors.lastname: Whitehurst
mesh_terms: D000818:Animals; D001343:Autophagy; D000071187:Autophagy-Related Protein 5 / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D057167:Claudins / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*
chemical_list: C502778:ATG5 protein, human; D000071187:Autophagy-Related Protein 5; D057167:Claudins; C551842:salt-inducible kinase-2, human; D017346:Protein Serine-Threonine Kinases