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Pan-HDAC inhibition by panobinostat mediates chemosensitization to carboplatin in non-small cell lung cancer via attenuation of EGFR signaling. (Cancer Lett, Jan 2018)

Wang L1, Syn NL2, Subhash VV3, Any Y4, Thuya WL3, Cheow E3, Kong L3, Yu F5, Peethala PC3, Wong AL2, Laljibhai HJ3, Chinnathambi A6, Ong PS7, Ho PC7, Sethi G8, Yong WP9, Goh BC10.

Author information
1 Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
2 Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore.
3 Cancer Science Institute of Singapore, National University of Singapore, Singapore.
4 Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore.
5 Department of Otolaryngology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
6 Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia.
7 Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore.
8 Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
9 Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore.
10 Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore.

Abstract
Accumulating evidence has implicated the aberrant regulation of histone deacetylases (HDACs) as a nexus for multiple cancer hallmarks and in mediating tumor adaptation and resistance to genotoxic chemotherapy, suggesting a rational pairing of HDAC inhibitors with DNA damaging chemotherapeutic agents in the treatment of human malignancies. Here we report that panobinostat (LBH589), a potent pan-HDAC inhibitor, effectively curbed the proliferation of non-small cell lung cancer (NSCLC) cell lines A549, Calu-1, H226, H460, H838 and SKMES-1 at IC50 concentrations between 4 and 31 nmol/L via pleiotropic mechanisms, including crosstalk with EGFR signal transduction cascades. Combination therapy with carboplatin elicited rapid tumor cell kill and effectively restrained anchorage-independent clonogenic survival to a considerably greater extent over either monotherapy. The administration of carboplatin and panobinostat at clinically relevant doses to NOD-SCID xenograft mice drastically stalled disease progression by 92% as compared with negative control (P = .0026), but significant less as 28% and 54% with either carboplatin (P = .220) or panobinostat (P = .017) alone. These data demonstrate that panobinostat has strong anti-NSCLC activity and chemosensitizes tumors to carboplatin, thus justifying further evaluation of this combination approach in clinical trials.

KEYWORDS: Epigenetic therapy; Histone deacetylase inhibitors; LBH589; Non-small cell lung cancer; Panobinostat

PMID: 29306016