title: LRIG1 modulates cancer cell sensitivity to Smac mimetics by regulating TNFα expression and receptor tyrosine kinase signaling.
abstract: Smac mimetics block inhibitor of apoptosis proteins to trigger TNFα-dependent apoptosis in cancer cells. However, only a small subset of cancer cells seem to be sensitive to Smac mimetics and even sensitive cells can develop resistance. Herein, we elucidated mechanisms underlying the intrinsic and acquired resistance of cancer cells to Smac mimetics. In vitro and in vivo investigations revealed that the expression of the cell surface protein LRIG1, a negative regulator of receptor tyrosine kinases (RTK), is downregulated in resistant derivatives of breast cancer cells sensitive to Smac mimetics. RNA interference-mediated downregulation of LRIG1 markedly attenuated the growth inhibitory activity of the Smac mimetic SM-164 in drug-sensitive breast and ovarian cancer cells. Furthermore, LRIG1 downregulation attenuated TNFα gene expression induced by Smac mimetics and increased the activity of multiple RTKs, including c-Met and Ron. The multitargeted tyrosine kinase inhibitors Crizotinib and GSK1363089 greatly enhanced the anticancer activity of SM-164 in all resistant cell derivatives, with the combination of SM-164 and GSK1363089 also completely inhibiting the outgrowth of resistant tumors in vivo. Together, our findings show that both upregulation of RTK signaling and attenuated TNFα expression caused by LRIG1 downregulation confers resistance to Smac mimetics, with implications for a rational combination strategy.
authors.affiliation: University of Michigan Comprehensive Cancer Center and Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Longchuan
authors.initials: L
authors.lastname: Bai
authors.forename: Donna
authors.initials: D
authors.lastname: McEachern
authors.forename: Chao-Yie
authors.initials: CY
authors.lastname: Yang
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Lu
authors.forename: Haiying
authors.initials: H
authors.lastname: Sun
authors.forename: Shaomeng
authors.initials: S
authors.lastname: Wang
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D014230:Triazoles / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D051017:Apoptosis Regulatory Proteins; D019086:Bridged Bicyclo Compounds, Heterocyclic; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; C484445:LRIG1 protein, human; D008562:Membrane Glycoproteins; D024101:Mitochondrial Proteins; C533467:SM 164; D014230:Triazoles; D014409:Tumor Necrosis Factor-alpha; D020794:Receptor Protein-Tyrosine Kinases