Dramatic antitumor effects of the dual MET/RON small-molecule inhibitor LY2801653 in non-small cell lung cancer

Ichiro Kawada, Rifat Hasina, Qudsia Arif, Jeffrey Mueller, Erin Smithberger, Aliya N. Husain, Everett E. Vokes, Ravi Salgia

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Lung cancer is a heterogeneous disease encompassing a wide array of genetic abnormalities. The MET receptor tyrosine kinase is altered in many lung cancers, especially non-small cell lung cancer (NSCLC), and clinical trials of MET inhibitors that are under way are documenting cases of acquired resistance. On the basis of the evidence that the RON tyrosine kinase receptor can also be overexpressed in NSCLC, we evaluated the potentMET/ RONdual kinase inhibitor LY2801653 in this setting. LY2801653 wasmore efficacious than theMET/ALK/RON/ROS inhibitor crizotinib with a distinct pattern of downstreamsignaling effects. Using the PamGene platform, we found that inhibition ofMET andRONwas associated with decreased phosphorylation of CBL, PI3K, and STAT3. In classic and orthotopicmouse xenograftmodels of lung cancer, LY2801653 decreased tumor growth, dramatically inhibiting mitotic events and angiogenesis. Taken together, our results argued that specific targeting of theMET/RON kinases could provide robust inhibition of cell proliferation and tumor outgrowth in multiple in vitro and in vivo models of NSCLC. These findings offer a robust preclinical proof of concept for MET/RON targeting by LY2801653 as a promising small-molecule modality to treat NSCLC.

Original languageEnglish
Pages (from-to)884-895
Number of pages12
JournalCancer Research
Volume74
Issue number3
DOIs
Publication statusPublished - 2014 Feb 1
Externally publishedYes

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Non-Small Cell Lung Carcinoma
Lung Neoplasms
Phosphotransferases
Proto-Oncogene Proteins c-met
Receptor Protein-Tyrosine Kinases
Phosphatidylinositol 3-Kinases
Neoplasms
Phosphorylation
Cell Proliferation
Clinical Trials
N-(3-fluoro-4-((1-methyl-6-(1H-pyrazol-4-yl)-1H-indazol-5 yl)oxy)phenyl)-1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide
rice bran saccharide
Growth

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Dramatic antitumor effects of the dual MET/RON small-molecule inhibitor LY2801653 in non-small cell lung cancer. / Kawada, Ichiro; Hasina, Rifat; Arif, Qudsia; Mueller, Jeffrey; Smithberger, Erin; Husain, Aliya N.; Vokes, Everett E.; Salgia, Ravi.

In: Cancer Research, Vol. 74, No. 3, 01.02.2014, p. 884-895.

Research output: Contribution to journalArticle

Kawada, I, Hasina, R, Arif, Q, Mueller, J, Smithberger, E, Husain, AN, Vokes, EE & Salgia, R 2014, 'Dramatic antitumor effects of the dual MET/RON small-molecule inhibitor LY2801653 in non-small cell lung cancer', Cancer Research, vol. 74, no. 3, pp. 884-895. https://doi.org/10.1158/0008-5472.CAN-12-3583
Kawada, Ichiro ; Hasina, Rifat ; Arif, Qudsia ; Mueller, Jeffrey ; Smithberger, Erin ; Husain, Aliya N. ; Vokes, Everett E. ; Salgia, Ravi. / Dramatic antitumor effects of the dual MET/RON small-molecule inhibitor LY2801653 in non-small cell lung cancer. In: Cancer Research. 2014 ; Vol. 74, No. 3. pp. 884-895.
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