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

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.

• 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 Jänne, Kwok-Kin Wong
• Journal: Cancer research (Cancer Res) Vol. 70 Issue 23 Pg. 9827-36 (Dec 01 2010) ISSN: 1538-7445 [Electronic] United States
• PMID: 20952506 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• EML4-ALK fusion protein, human
• HSP90 Heat-Shock Proteins
• NVP-TAE684
• Oncogene Proteins, Fusion
• Phosphoinositide-3 Kinase Inhibitors
• Pyrimidines
• Carboplatin
• ALK protein, human
• Alk protein, mouse
• Anaplastic Lymphoma Kinase
• Protein-Tyrosine Kinases
• Receptor Protein-Tyrosine Kinases
• Mitogen-Activated Protein Kinase Kinases
• Paclitaxel

Topics

• Adenocarcinoma (drug therapy, genetics, pathology)
• Amino Acid Sequence
• Anaplastic Lymphoma Kinase
• Animals
• Antineoplastic Agents (pharmacology)
• Carboplatin (pharmacology)
• Cell Line, Tumor
• Cluster Analysis
• Female
• Gene Expression Profiling
• HSP90 Heat-Shock Proteins (antagonists & inhibitors, genetics, metabolism)
• Humans
• Lung Neoplasms (drug therapy, genetics, pathology)
• Male
• Mice
• Mice, Transgenic
• Mitogen-Activated Protein Kinase Kinases (antagonists & inhibitors, genetics, metabolism)
• Molecular Sequence Data
• Oncogene Proteins, Fusion (genetics, metabolism)
• Paclitaxel (pharmacology)
• Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Protein-Tyrosine Kinases (antagonists & inhibitors, genetics, metabolism)
• Pyrimidines (pharmacology)
• Receptor Protein-Tyrosine Kinases
• Survival Analysis
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays