Inhibition of ALK, PI3K/MEK, and HSP90 in Murine Lung Adenocarcinoma Induced by EML4-ALK Fusion Oncogene

Overview

Journal Cancer Res

Specialty Oncology

Date 2010 Oct 19

PMID 20952506

Citations 99

Authors

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 Shapiro

Pasi A Janne

Kwok-Kin Wong

Affiliations

Soon will be listed here.

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 KRASor 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.

Citing Articles

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