A Functional Landscape of Resistance to ALK Inhibition in Lung Cancer

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.

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A Functional Landscape of Resistance to ALK Inhibition in Lung Cancer

Published Date:

Mar 09 2015

Source:

Cancer Cell. 2015; 27(3):397-408

Language:

English

[PDF-2.41 MB]

Details:

Alternative Title:

Cancer Cell

Personal Author:

Wilson, Frederick H. ; Johannessen, Cory M. ; Piccioni, Federica ; Tamayo, Pablo ; Kim, Jong Wook ; ... More ▼

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:

[+]

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 ▼

Collection(s):

CDC Public Access

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