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Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer


Human non–small cell lung cancers (NSCLCs) with activating mutations in EGFR frequently respond to treatment with EGFR-targeted tyrosine kinase inhibitors (TKIs), such as erlotinib, but responses are not durable, as tumors acquire resistance. Secondary mutations in EGFR (such as T790M) or upregulation of the MET kinase are found in over 50% of resistant tumors. Here, we report increased activation of AXL and evidence for epithelial-to-mesenchymal transition (EMT) in multiple in vitro and in vivo EGFR-mutant lung cancer models with acquired resistance to erlotinib in the absence of the EGFR p.Thr790Met alteration or MET activation. Genetic or pharmacological inhibition of AXL restored sensitivity to erlotinib in these tumor models. Increased expression of AXL and, in some cases, of its ligand GAS6 was found in EGFR-mutant lung cancers obtained from individuals with acquired resistance to TKIs. These data identify AXL as a promising therapeutic target whose inhibition could prevent or overcome acquired resistance to EGFR TKIs in individuals with EGFR-mutant lung cancer.

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Figure 1: AXL is overexpressed in EGFR-mutant NSCLC tumor xenografts with acquired resistance to erlotinib.
Figure 2: AXL overexpression is necessary for acquired resistance to erlotinib treatment in EGFR-mutant NSCLC tumors in vivo.
Figure 3: AXL upregulation is necessary and sufficient for acquired resistance to erlotinib in EGFR-mutant NSCLC cellular models.
Figure 4: AXL-mediated erlotinib resistance occurs in association with EMT in EGFR-mutant NSCLC cellular models.
Figure 5: AXL upregulation occurs in human EGFR-mutant NSCLCs with acquired resistance to EGFR TKIs.

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The authors thank K. Shokat for assistance with structural modeling of the AXL gatekeeper mutation, W. Polkinghorn, J. Wongvipat and E. Chan for advice and technical assistance and S. Edelheit of the Case Genomics Center for technical assistance. This work was supported by the Korean Health Technology R&D Project (grant A102059 to J.C.L.), the US National Institutes of Health (K08 1K08CA154787 to T.G.B. and P01 CA129243 to M.L.), a Uniting Against Lung Cancer Research Award, a National Lung Cancer Partnership Young Investigator Award (to T.G.B.), a grant from the La Caixa Foundation (to R.R.) and an American Cancer Society Research Scholar Grant (RSG-08-303-01 to B.H.).

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Z.Z., J.C.L., L.L., V.A., T.L., M.A.-R., X.W., A.D.L., J.K.R., Y.J.C., C.-M.C., Y.S.P., S.-W.K., D.H.L., J.-S.L., P.M. and T.G.B. performed in vitro experiments. J.C.L., V.O., S.J.J., Y.S.P. and C.C. analyzed clinical specimens. M.A. and T.G.B. analyzed clinical data. P.M. and T.G.B. performed in vivo experiments. W.S.K., P.C.M., M.L., T.J.B., V.A.M., C.S., P.M., M.T., R.R., B.H. and T.G.B. analyzed in vitro and in vivo data. B.H. and T.G.B. wrote the manuscript.

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Correspondence to Balazs Halmos or Trever G Bivona.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–14 and Supplementary Tables 4 and 5 (PDF 11391 kb)

Supplementary Table 1

Gene expression changes observed in erlotinib resistant HCC827 tumor xenografts by combined analysis. (XLS 117 kb)

Supplementary Table 2

Gene expression changes observed in erlotinib resistant HCC827 tumor xenografts. (XLS 4588 kb)

Supplementary Table 3

Gene expression changes observed in erlotinib resistant HCC827 cell lines. (XLS 203 kb)

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Zhang, Z., Lee, J., Lin, L. et al. Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. Nat Genet 44, 852–860 (2012).

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