The HSP90 inhibitor, NVP-AUY922, attenuates intrinsic PI3K inhibitor resistance in KRAS-mutant non-small cell lung cancer.

Abstract

More than 25% of non-small cell lung cancers (NSCLCs) carry mutations in KRAS, one of the most common oncogenic drivers in this disease. KRAS-mutant NSCLC responds poorly to currently available therapies; therefore, novel treatment strategies are needed. Here, we describe a particularly promising targeted therapeutic strategy against KRAS mutation-harboring NSCLC intrinsically resistant to treatment by PI3K inhibition. We found that intrinsic resistance to PI3K inhibition derived from RAF/MEK/ERK and RSK activation, bypassing blockage of the PI3K/AKT/mTOR pathway. The HSP90 inhibitor AUY922 suppressed both PI3K/AKT/mTOR and RAF/MEK/ERK signaling, rendering cells sensitive to a PI3K inhibitor (omipalisib, GSK458). Combining these two drugs achieved a synergistic effect, even using only sub-therapeutic concentrations. Dual inhibition of the HSP90 and PI3K signaling pathways with sub-therapeutic doses of these combined anticancer drugs may represent a potent treatment strategy for KRAS-mutant NSCLC with intrinsic resistance to PI3K inhibition.

• Authors: Kang-Seo Park, Hannah Yang, Junyoung Choi, Seyoung Seo, Deokhoon Kim, Chang Hoon Lee, Hanwool Jeon, Sang-We Kim, Dae Ho Lee
• Journal: Cancer letters (Cancer Lett) Vol. 406 Pg. 47-53 (10 10 2017) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 28797845 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier B.V. All rights reserved.

Chemical References

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

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Carcinoma, Non-Small-Cell Lung (drug therapy, metabolism, pathology)
• Cell Line, Tumor
• Drug Resistance, Neoplasm (drug effects)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• HSP90 Heat-Shock Proteins (antagonists & inhibitors)
• Humans
• Isoxazoles (pharmacology)
• Lung Neoplasms (drug therapy, metabolism, pathology)
• Mice
• Mice, Inbred BALB C
• Mutation (genetics)
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins p21(ras) (genetics)
• Resorcinols (pharmacology)
• Signal Transduction (drug effects)