The HSP90 inhibitor, NVP-AUY922, sensitizes KRAS-mutant non-small cell lung cancer with intrinsic resistance to MEK inhibitor, trametinib

Kang-Seo Park; Bora Oh; Mi-Hee Lee; Ky-Youb Nam; Hae Ran Jin; Hannah Yang; Junyoung Choi; Sang-We Kim; Dae Ho Lee

doi:10.1016/j.canlet.2015.12.015

The HSP90 inhibitor, NVP-AUY922, sensitizes KRAS-mutant non-small cell lung cancer with intrinsic resistance to MEK inhibitor, trametinib

Cancer Lett. 2016 Mar 1;372(1):75-81. doi: 10.1016/j.canlet.2015.12.015. Epub 2015 Dec 23.

Authors

Kang-Seo Park¹, Bora Oh², Mi-Hee Lee², Ky-Youb Nam¹, Hae Ran Jin¹, Hannah Yang³, Junyoung Choi¹, Sang-We Kim², Dae Ho Lee⁴

Affiliations

¹ Institute for Innovative Cancer Research, College of Medicine, Asan Medical Center, University of Ulsan, Seoul 138-736, Republic of Korea.
² Department of Oncology, Asan Medical Center, Seoul, Republic of Korea.
³ Department of Oncology, Asan Medical Center, Seoul, Republic of Korea; Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
⁴ Institute for Innovative Cancer Research, College of Medicine, Asan Medical Center, University of Ulsan, Seoul 138-736, Republic of Korea; Department of Oncology, Asan Medical Center, Seoul, Republic of Korea. Electronic address: leedaeho@amc.seoul.kr.

PMID: 26723875
DOI: 10.1016/j.canlet.2015.12.015

Abstract

RAS-driven tumors are often difficult to treat with conventional therapies and therefore, novel treatment strategies are necessary. The present study describes a promising targeted therapeutic strategy against non-small cell lung cancer (NSCLC) harboring KRAS mutations, which has intrinsic resistance to MEK inhibition. Results showed that intrinsic resistance to MEK inhibition occurred via high AKT expression by PI3K activation as a bypass pathway. The HSP90 inhibitor AUY922 suppressed PI3K-AKT-mTOR and RAF-MEK-ERK, and rendered cells sensitive to trametinib (GSK1120212). Synergy from the combination of the two drugs was observed in only sub-therapeutic concentrations of either drug. Dual inhibition of the HSP90 and MEK signaling pathways with sub-therapeutic doses may represent a potent therapeutic strategy to treat KRAS-mutant NSCLC with intrinsic resistance to MEK inhibition and to resolve the toxicity observed upon dual inhibition of AKT and MEK at therapeutic doses in clinical trials.

Keywords: Combination therapy; HSP90 inhibitor; KRAS mutation; MEK inhibitor; NSCLC.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Carcinoma, Non-Small-Cell Lung / drug therapy*
Carcinoma, Non-Small-Cell Lung / enzymology
Carcinoma, Non-Small-Cell Lung / genetics
Carcinoma, Non-Small-Cell Lung / pathology
Cell Line, Tumor
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm*
Drug Synergism
Female
HSP90 Heat-Shock Proteins / antagonists & inhibitors*
HSP90 Heat-Shock Proteins / metabolism
Humans
Isoxazoles / pharmacology*
Lung Neoplasms / drug therapy*
Lung Neoplasms / enzymology
Lung Neoplasms / genetics
Lung Neoplasms / pathology
Mice, Inbred BALB C
Mice, Nude
Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors*
Mitogen-Activated Protein Kinase Kinases / metabolism
Mutation*
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins p21(ras) / genetics*
Pyridones / pharmacology*
Pyrimidinones / pharmacology*
Resorcinols / pharmacology*
Signal Transduction / drug effects
Time Factors
Tumor Burden / drug effects
Xenograft Model Antitumor Assays

Substances

5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide
HSP90 Heat-Shock Proteins
Isoxazoles
KRAS protein, human
Protein Kinase Inhibitors
Pyridones
Pyrimidinones
Resorcinols
trametinib
Mitogen-Activated Protein Kinase Kinases
Proto-Oncogene Proteins p21(ras)