Editors' ChoiceCancer

New targets for ALK-driven lung cancer

Sci. Signal.  17 Mar 2015:
Vol. 8, Issue 368, pp. ec61
DOI: 10.1126/scisignal.aab1146

A fusion protein involving the tyrosine kinase receptor ALK promotes nonsmall cell lung cancer (NSCLC), but some patients exhibit resistance to ALK inhibitors. Wilson et al. performed a functional genomic screen and identified genes that when overexpressed conferred resistance to ALK inhibitors in the NSCLC line H3122. Among the validated genes were those encoding the HER3 (human epidermal growth factor receptor) ligand neuregulin (NRG1) and several members of the purinergic receptor P2Y family, which are GPCRs (G protein–coupled receptors). Upon activation, HER3 dimerizes with HER2 to transduce the signal. Resistance to the ALK inhibitor TAE684 in H3122 cells overexpressing NRG1 was decreased by coapplication of the HER2 inhibitor lapatinib. ALK inhibitor-resistant H3122 cells overexpressing P2Y1 or P2Y2 had increased abundance of activated protein kinase C δ (PKCδ), and combining the ALK inhibitor crizotinib with a pan-PKC inhibitor decreased the growth of P2Y1- or P2Y2-transfected H3122 colonies. Exposing parental H3122 cells to a nonspecific PKC agonist decreased the toxicity of the ALK inhibitor ceritinib, and the abundance of activated PKCδ increased in parental cells cultured under the selective pressure of ceritinib. GSEA (gene set enrichment analysis) identified expression signatures associated with NRG1 or P2Y receptor signaling in crizotinib-resistant lung tumor tissue compared with treatment-naïve tumors. The findings reveal new potential therapeutic targets for NSCLC patients resistant to ALK inhibitors.

F. H. Wilson, C. M. Johannessen, F. Piccioni, P. Tamayo, J. W. Kim, E. M. Van Allen, S. M. Corsello, M. Capelletti, A. Calles, M. Butaney, T. Sharifnia, S. B. Gabriel, J. P. Mesirov, W. C. Hahn, J. A. Engelman, M. Meyerson, D. E. Root, P. A. Jänne, L. A. Garraway, A functional landscape of resistance to ALK inhibition in lung cancer. Cancer Cell 27, 397–408 (2015). [PubMed]