Details

Autor(en) / Beteiligte

• 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.

Titel

A Functional Landscape of Resistance to ALK Inhibition in Lung Cancer

Ist Teil von

• Cancer cell, 2015-03, Vol.27 (3), p.397-408

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2015

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •Multiple genes and pathways are sufficient to drive resistance to ALK inhibition•A subset also confers resistance to EGFR inhibition in EGFR mutant lung cancer•P2Y receptors mediate ALK inhibitor resistance in part via protein kinase C•EGFR, HER2, and P2Y gene signatures are enriched in crizotinib-resistant tumors Wilson et al. identify mechanisms sufficient to confer resistance to ALK inhibitors, including crizotinib and ceritinib, in ALK-dependent NSCLC and suggest roles for members of the P2Y purinergic receptor family of G-protein-coupled receptors and PKC signaling.