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Combined EGFR/MET or EGFR/HSP90 inhibition is effective in the treatment of lung cancers codriven by mutant EGFR containing T790M and MET.

Publication ,  Journal Article
Xu, L; Kikuchi, E; Xu, C; Ebi, H; Ercan, D; Cheng, KA; Padera, R; Engelman, JA; Jänne, PA; Shapiro, GI; Shimamura, T; Wong, K-K
Published in: Cancer Res
July 1, 2012

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.

Duke Scholars

Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

July 1, 2012

Volume

72

Issue

13

Start / End Page

3302 / 3311

Location

United States

Related Subject Headings

  • Signal Transduction
  • Real-Time Polymerase Chain Reaction
  • RNA, Messenger
  • Proto-Oncogene Proteins c-met
  • Protein-Tyrosine Kinases
  • Protein Kinase Inhibitors
  • Oncology & Carcinogenesis
  • Mutation
  • Mice, Transgenic
  • Mice
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Xu, L., Kikuchi, E., Xu, C., Ebi, H., Ercan, D., Cheng, K. A., … Wong, K.-K. (2012). Combined EGFR/MET or EGFR/HSP90 inhibition is effective in the treatment of lung cancers codriven by mutant EGFR containing T790M and MET. Cancer Res, 72(13), 3302–3311. https://doi.org/10.1158/0008-5472.CAN-11-3720
Xu, Lu, Eiki Kikuchi, Chunxiao Xu, Hiromichi Ebi, Dalia Ercan, Katherine A. Cheng, Robert Padera, et al. “Combined EGFR/MET or EGFR/HSP90 inhibition is effective in the treatment of lung cancers codriven by mutant EGFR containing T790M and MET.Cancer Res 72, no. 13 (July 1, 2012): 3302–11. https://doi.org/10.1158/0008-5472.CAN-11-3720.
Xu L, Kikuchi E, Xu C, Ebi H, Ercan D, Cheng KA, et al. Combined EGFR/MET or EGFR/HSP90 inhibition is effective in the treatment of lung cancers codriven by mutant EGFR containing T790M and MET. Cancer Res. 2012 Jul 1;72(13):3302–11.
Xu, Lu, et al. “Combined EGFR/MET or EGFR/HSP90 inhibition is effective in the treatment of lung cancers codriven by mutant EGFR containing T790M and MET.Cancer Res, vol. 72, no. 13, July 2012, pp. 3302–11. Pubmed, doi:10.1158/0008-5472.CAN-11-3720.
Xu L, Kikuchi E, Xu C, Ebi H, Ercan D, Cheng KA, Padera R, Engelman JA, Jänne PA, Shapiro GI, Shimamura T, Wong K-K. Combined EGFR/MET or EGFR/HSP90 inhibition is effective in the treatment of lung cancers codriven by mutant EGFR containing T790M and MET. Cancer Res. 2012 Jul 1;72(13):3302–3311.

Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

July 1, 2012

Volume

72

Issue

13

Start / End Page

3302 / 3311

Location

United States

Related Subject Headings

  • Signal Transduction
  • Real-Time Polymerase Chain Reaction
  • RNA, Messenger
  • Proto-Oncogene Proteins c-met
  • Protein-Tyrosine Kinases
  • Protein Kinase Inhibitors
  • Oncology & Carcinogenesis
  • Mutation
  • Mice, Transgenic
  • Mice