Details:

Alternative Title:
Cancer Cell
Personal Author:
Wilson, Frederick H. ; Johannessen, Cory M. ; Piccioni, Federica ; Tamayo, Pablo ; Kim, Jong Wook ; ... More +
Wilson, Frederick H. ; Johannessen, Cory M. ; Piccioni, Federica ; Tamayo, Pablo ; Kim, Jong Wook ; Van Allen, Eliezer M. ; Corsello, Steven M. ; Capelletti, Marzia ; Calles, Antonio ; Butaney, Mohit ; Sharifnia, Tanaz ; Gabriel, Stacey B. ; Mesirov, Jill P. ; Hahn, William C. ; Engelman, Jeffrey A. ; Meyerson, Matthew ; Root, David E. ; Jänne, Pasi A. ; Garraway, Levi A. ; Less -
Description:
We conducted a large-scale functional genetic study to characterize mechanisms of resistance to ALK inhibition in ALK-dependent lung cancer cells. We identify members of known resistance pathways and additional putative resistance drivers. Among the latter were members of the P2Y purinergic receptor family of G-protein-coupled receptors (P2Y1, P2Y2, and P2Y6). P2Y receptors mediated resistance in part through a protein-kinase-C (PKC)-dependent mechanism. Moreover, PKC activation alone was sufficient to confer resistance to ALK inhibitors, whereas combined ALK and PKC inhibition restored sensitivity. We observed enrichment of gene signatures associated with several resistance drivers (including P2Y receptors) in crizotinib-resistant ALK-rearranged lung tumors compared to treatment-naive controls, supporting a role for these identified mechanisms in clinical ALK inhibitor resistance.
Subject:
[+]
Anaplastic Lymphoma Kinase
Article
Carcinoma, Non-Small-Cell Lung
Cell Line, Tumor
Crizotinib
Drug Resistance, Neoplasm
ErbB Receptors
Humans
Lung Neoplasms
Pyrazoles
Pyridines
Receptor, ErbB-2
Receptor Protein-Tyrosine Kinases
Receptors, Purinergic P2Y
Signal Transduction

Source:
Cancer Cell. 2015; 27(3):397-408
Pubmed ID:
25759024
Pubmed Central ID:
PMC4398996
Document Type:
Journal Article ;
Funding:
NIH R01 CA154480/CA/NCI NIH HHS/United States ; R01 GM074024/GM/NIGMS NIH HHS/United States ; U54 HG003067/HG/NHGRI NIH HHS/United States ; #5U54HG003067-11/HG/NHGRI NIH HHS/United States ; GM074024/GM/NIGMS NIH HHS/United States ; ... More +
NIH R01 CA154480/CA/NCI NIH HHS/United States ; R01 GM074024/GM/NIGMS NIH HHS/United States ; U54 HG003067/HG/NHGRI NIH HHS/United States ; #5U54HG003067-11/HG/NHGRI NIH HHS/United States ; GM074024/GM/NIGMS NIH HHS/United States ; U54 HG006093/HG/NHGRI NIH HHS/United States ; NIH R01 CA136851/CA/NCI NIH HHS/United States ; T32 CA009172/CA/NCI NIH HHS/United States ; P01 CA154303/CA/NCI NIH HHS/United States ; U01 CA176058/CA/NCI NIH HHS/United States ; DP2 0D002750/DP/NCCDPHP CDC HHS/United States ; R33 CA155554/CA/NCI NIH HHS/United States ; R01 CA154480/CA/NCI NIH HHS/United States ; U54 CA112962/CA/NCI NIH HHS/United States ; NIH 5R33CA155554-03/CA/NCI NIH HHS/United States ; R01 CA121941/CA/NCI NIH HHS/United States ; R01 CA136851/CA/NCI NIH HHS/United States ; Less -
Collection(s):
CDC Public Access
Main Document Checksum:
[+]
urn:sha256:15f854f2c271178fcdefac025e80f80b10e0a24c7d39f0c00c945455251bf444
File Type:

Supporting Files

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