A functional landscape of resistance to ALK inhibition in lung cancer

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

doi:10.1016/j.ccell.2015.02.005

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.

Authors

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

Affiliations

¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
² The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
³ Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
⁴ Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.
⁵ Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
⁶ Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
⁷ Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; The Broad Institute of MIT and Harvard, 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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Anaplastic Lymphoma Kinase
Carcinoma, Non-Small-Cell Lung / drug therapy
Carcinoma, Non-Small-Cell Lung / genetics*
Carcinoma, Non-Small-Cell Lung / pathology
Cell Line, Tumor
Crizotinib
Drug Resistance, Neoplasm / genetics*
ErbB Receptors / genetics
Humans
Lung Neoplasms / drug therapy
Lung Neoplasms / genetics*
Lung Neoplasms / pathology
Pyrazoles / pharmacology*
Pyrazoles / therapeutic use
Pyridines / pharmacology*
Pyridines / therapeutic use
Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
Receptor Protein-Tyrosine Kinases / genetics
Receptor Protein-Tyrosine Kinases / metabolism
Receptor, ErbB-2 / genetics
Receptors, Purinergic P2Y / genetics
Signal Transduction / drug effects
Signal Transduction / genetics

Substances

Pyrazoles
Pyridines
Receptors, Purinergic P2Y
Crizotinib
ALK protein, human
Anaplastic Lymphoma Kinase
EGFR protein, human
ERBB2 protein, human
ErbB Receptors
Receptor Protein-Tyrosine Kinases
Receptor, ErbB-2

Associated data

dbGaP/PHS000855.V1.P1

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding