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 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. Cancer Res; 70(23); 9827-36. Ó2010 AACR.

Crystal structure of EML1 reveals the basis for Hsp90 dependence of oncogenic EML4-ALK by disruption of an atypical β-propeller domain

“…This makes them dependent on molecular chaperones to remain stable. Indeed, EML4-ALK variant 1 has been shown to be highly unstable, and it may be more sensitive to Hsp90 inhibition than any other client protein yet observed (8,9,25). The sensitivity of variants 1 and 2 are due to protein mis-folding resulting in exposure of hydrophobic residues that recruit Hsp90, which is supported by the observation that this sensitivity is not found in variants 3 and 5 (12).…”

FGFR3 Translocations in Bladder Cancer: Differential Sensitivity to HSP90 Inhibition Based on Drug Metabolism

“…However, a recurring theme in the clinical experience with many targeted kinase inhibitor drugs, including imatinib and crizotinib, is that their long-term efficacy is often hampered by the invariable development of acquired resistance, commonly arising due to the acquisition of secondary mutations in their respective kinase targets (34,35). We and others have previously shown that HSP90 inhibition is an effective approach for overcoming oncogenic EML4-ALK activity in non-small cell lung cancer (18,36,37). Significantly, ganetespib also displayed potent activity against a variety of acquired ALK mutations that confer crizotinib resistance in multiple experimental models and in the clinical setting (18).…”

Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK

“…In all cases, the fusion partner (e.g., EML4) is believed to mediate ligand-independent oligomerization of ALK, resulting in constitutive ALK kinase activation (2)(3)(4). In cell line and genetically engineered mouse models, EML4-ALK serves as a potent oncogenic "driver," and cancers with this translocation are highly sensitive to ALK kinase inhibition (5,6). Recently, a tyrosine kinase inhibitor (TKI) targeting ALK, crizotinib (PF-02341066), was examined in a phase 1 trial (7).…”