From Harvard: A Functional Landscape of Resistance to ALK Inhibition in Lung Cancer

Cancer Cell. 2015 Mar 9;27(3):397-408. doi: 10.1016/j.ccell.2015.02.005.

A Functional Landscape of Resistance to ALK Inhibition in Lung Cancer.

Wilson FH1, Johannessen CM2, Piccioni F2, Tamayo P2, Kim JW1, Van Allen EM1, Corsello SM1, Capelletti M3, Calles A3, Butaney M3, Sharifnia T1, Gabriel SB2, Mesirov JP2, Hahn WC1, Engelman JA4, Meyerson M5, Root DE2, Jänne PA6, Garraway LA7.

Author information

• 1Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; The Broad Institute of MIT andHarvard, Cambridge, MA 02142, USA.
• 2The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
• 3Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
• 4Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.
• 5Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; The Broad Institute of MIT andHarvard, Cambridge, MA 02142, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
• 6Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Belfer Institute for AppliedCancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
• 7Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; The Broad Institute of MIT andHarvard, Cambridge, MA 02142, USA. Electronic address: levi_garraway@dfci.harvard.edu.

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.