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Journal Article

A functional landscape of resistance to ALK inhibition in lung cancer

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.

Frederick H Wilson
Cory M Johannessen
Federica Piccioni
Pablo Tamayo
Jong Wook Kim
Eliezer M Van Allen
Steven M Corsello
Marzia Capelletti
Antonio Calles
Mohit Butaney
Tanaz Sharifnia
Stacey B Gabriel
Jill P Mesirov
William C Hahn
Jeffrey A Engelman
Matthew Meyerson
David E Root
Pasi A Jänne
Levi A Garraway
Journal Name
Cancer Cell
Publication Date
March, 2015