Simvastatin Overcomes Resistance to Tyrosine Kinase Inhibitors in Patient-derived, Oncogene-driven Lung Adenocarcinoma Models

Author:

Ma Weijie1ORCID,Wei Sixi1ORCID,Li Qianping1ORCID,Zeng Jie1ORCID,Xiao Wenwu23ORCID,Zhou Chihong4ORCID,Yoneda Ken Y.5ORCID,Zeki Amir A.25ORCID,Li Tianhong12ORCID

Affiliation:

1. 1Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis School of Medicine, University of California Davis Comprehensive Cancer Center, Sacramento, California.

2. 2Medical Service, Veterans Affairs Northern California Health Care System, Mather, California.

3. 3Department of Biochemistry and Molecular Medicine, University of California Davis, Sacramento, California.

4. 4Department of Pathology and Laboratory Medicine, University of California Davis School of Medicine, Sacramento, California.

5. 5Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, University of California Davis School of Medicine, UC Davis Lung Center, Sacramento, California.

Abstract

Abstract There is an unmet clinical need to develop novel strategies to overcome resistance to tyrosine kinase inhibitors (TKI) in patients with oncogene-driven lung adenocarcinoma (LUAD). The objective of this study was to determine whether simvastatin could overcome TKI resistance using the in vitro and in vivo LUAD models. Human LUAD cell lines, tumor cells, and patient-derived xenograft (PDX) models from TKI-resistant LUAD were treated with simvastatin, either alone or in combination with a matched TKI. Tumor growth inhibition was measured by the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay and expression of molecular targets was assessed by immunoblots. Tumors were assessed by histopathology, IHC stain, immunoblots, and RNA sequencing. We found that simvastatin had a potent antitumor effect in tested LUAD cell lines and PDX tumors, regardless of tumor genotypes. Simvastatin and TKI combination did not have antagonistic cytotoxicity in these LUAD models. In an osimertinib-resistant LUAD PDX model, simvastatin and osimertinib combination resulted in a greater reduction in tumor volume than simvastatin alone (P < 0.001). Immunoblots and IHC stain also confirmed that simvastatin inhibited TKI targets. In addition to inhibiting 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, RNA sequencing and Western blots identified the proliferation, migration, and invasion-related genes (such as PI3K/Akt/mTOR, YAP/TAZ, focal adhesion, extracellular matrix receptor), proteasome-related genes, and integrin (α3β1, αvβ3) signaling pathways as the significantly downregulated targets in these PDX tumors treated with simvastatin and a TKI. The addition of simvastatin is a safe approach to overcome acquired resistance to TKIs in several oncogene-driven LUAD models, which deserve further investigation.

Funder

Biomedical Laboratory Research and Development, VA Office of Research and Development

Office of Research and Development

Comprehensive Cancer Center, University of California, Davis

Publisher

American Association for Cancer Research (AACR)

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