Supplementary Figures 1-6 from Combined EGFR/MET or EGFR/HSP90 Inhibition Is Effective in the Treatment of Lung Cancers Codriven by Mutant EGFR Containing T790M and MET

Xu, Lu; Kikuchi, Eiki; Xu, Chunxiao; Ebi, Hiromichi; Ercan, Dalia; Cheng, Katherine A.; Padera, Robert; Engelman, Jeffrey A.; Jänne, Pasi A.; Shapiro, Geoffrey I.; Shimamura, Takeshi; Wong, Kwok-Kin

doi:10.1158/0008-5472.22391819.v1

00085472can113720-sup-f1-6_1410k.pdf (1.38 MB)

Supplementary Figures 1-6 from Combined EGFR/MET or EGFR/HSP90 Inhibition Is Effective in the Treatment of Lung Cancers Codriven by Mutant EGFR Containing T790M and MET

journal contribution

posted on 2023-03-30, 21:02 authored by Lu Xu, Eiki Kikuchi, Chunxiao Xu, Hiromichi Ebi, Dalia Ercan, Katherine A. Cheng, Robert Padera, Jeffrey A. Engelman, Pasi A. Jänne, Geoffrey I. Shapiro, Takeshi Shimamura, Kwok-Kin Wong

PDF file - 1.4MB, Supplemental Figure 1. MET is inducible in MET, TD/MET, and TL/MET models Supplemental Figure 2. Quantification of hMET expression in mouse models Supplemental Figure 3. Comparison of the tumor counts in mutant EGFR lung tumors with or without expression of hMET. Supplemental Figure 4. Representative MRI images prior to and after treatment in TL and TL/MET mice. Supplemental Figure 5. Xenografts of HCC827GR6 cells ectopically expressing EGFR E746_A750del/T790M are sensitive to the combination of WZ4002 and 17-DMAG. Supplemental Figure 6. The WZ4002/crizotinib or WZ4002/17-DMAG combinations suppress phosphorylation of EGFR, Akt, and Erk in TD and TD/MET to a greater extent than individual treatments

History

ARTICLE ABSTRACT

Tyrosine kinase inhibitors (TKI) that target the EGF receptor (EGFR) are effective in most non–small cell lung carcinoma (NSCLC) patients whose tumors harbor activating EGFR kinase domain mutations. Unfortunately, acquired resistance eventually emerges in these chronically treated cancers. Two of the most common mechanisms of acquired resistance to TKIs seen clinically are the acquisition of a secondary “gatekeeper” T790M EGFR mutation that increases the affinity of mutant EGFR for ATP and activation of MET to offset the loss of EGFR signaling. Although up to one-third of patient tumors resistant to reversible EGFR TKIs harbor concurrent T790M mutation and MET amplification, potential therapies for these tumors have not been modeled in vivo. In this study, we developed a preclinical platform to evaluate potential therapies by generating transgenic mouse lung cancer models expressing EGFR-mutant Del19-T790M or L858R-T790M, each with concurrent MET overexpression. We found that monotherapy targeting EGFR or MET alone did not produce significant tumor regression. In contrast, combination therapies targeting EGFR and MET simultaneously were highly efficacious against EGFR TKI–resistant tumors codriven by Del19-T790M or L858R-T790M and MET. Our findings therefore provide an in vivo model of intrinsic resistance to reversible TKIs and offer preclinical proof-of-principle that combination targeting of EGFR and MET may benefit patients with NSCLC. Cancer Res; 72(13); 3302–11. ©2012 AACR.