| Literature DB >> 25759024 |
Frederick H Wilson1, Cory M Johannessen2, Federica Piccioni2, Pablo Tamayo2, Jong Wook Kim1, Eliezer M Van Allen1, Steven M Corsello1, Marzia Capelletti3, Antonio Calles3, Mohit Butaney3, Tanaz Sharifnia1, Stacey B Gabriel2, Jill P Mesirov2, William C Hahn1, Jeffrey A Engelman4, Matthew Meyerson5, David E Root2, Pasi A Jänne6, Levi A Garraway7.
Abstract
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.Entities:
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Year: 2015 PMID： 25759024 PMCID： PMC4398996 DOI： 10.1016/j.ccell.2015.02.005
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743