Inhibition of ALK, PI3K/MEK, and HSP90 in murine lung adenocarcinoma induced by EML4-ALK fusion oncogene

Zhao Chen, Takaaki Sasaki, Xiaohong Tan, Julian Carretero, Takeshi Shimamura, Danan Li, Chunxiao Xu, Yuchuan Wang, Guillaume O. Adelmant, Marzia Capelletti, Hyun Joo Lee, Scott J. Rodig, Christa Borgman, Seung Il Park, Hyeong Ryul Kim, Robert Padera, Jarrod A. Marto, Nathanael S. Gray, Andrew L. Kung, Geoffrey I. ShapiroPasi A. Jänne, Kwok Kin Wong

Research output: Contribution to journalArticle

Abstract

Genetic rearrangements of the anaplastic lymphoma kinase (ALK) kinase occur in 3% to 13% of non-small cell lung cancer patients and rarely coexist with KRAS or EGFR mutations. To evaluate potential treatment strategies for lung cancers driven by an activated EML4-ALK chimeric oncogene, we generated a genetically engineered mouse model that phenocopies the human disease where this rearranged gene arises. In this model, the ALK kinase inhibitor TAE684 produced greater tumor regression and improved overall survival compared with carboplatin and paclitaxel, representing clinical standard of care. 18F-FDG-PET-CT scans revealed almost complete inhibition of tumor metabolic activity within 24 hours of TAE684 exposure. In contrast, combined inhibition of the PI3K/AKT and MEK/ERK1/2 pathways did not result in significant tumor regression. We identified EML4-ALK in complex with multiple cellular chaperones including HSP90. In support of a functional reliance, treatment with geldanamycin-based HSP90 inhibitors resulted in rapid degradation of EML4-ALK in vitro and substantial, albeit transient, tumor regression in vivo. Taken together, our findings define a murine model that offers a reliable platform for the preclinical comparison of combinatorial treatment approaches for lung cancer characterized by ALK rearrangement.

Original languageEnglish (US)
Pages (from-to)9827-9836
Number of pages10
JournalCancer Research
Volume70
Issue number23
DOIs
StatePublished - Dec 1 2010

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Chen, Z., Sasaki, T., Tan, X., Carretero, J., Shimamura, T., Li, D., Xu, C., Wang, Y., Adelmant, G. O., Capelletti, M., Lee, H. J., Rodig, S. J., Borgman, C., Park, S. I., Kim, H. R., Padera, R., Marto, J. A., Gray, N. S., Kung, A. L., ... Wong, K. K. (2010). Inhibition of ALK, PI3K/MEK, and HSP90 in murine lung adenocarcinoma induced by EML4-ALK fusion oncogene. Cancer Research, 70(23), 9827-9836. https://doi.org/10.1158/0008-5472.CAN-10-1671