PMID- 25077897
OWN - NLM
STAT- MEDLINE
DCOM- 20160307
LR  - 20240330
IS  - 1776-260X (Electronic)
IS  - 1776-2596 (Print)
IS  - 1776-2596 (Linking)
VI  - 10
IP  - 2
DP  - 2015 Jun
TI  - The HSP90 inhibitor ganetespib potentiates the antitumor activity of EGFR 
      tyrosine kinase inhibition in mutant and wild-type non-small cell lung cancer.
PG  - 235-45
LID - 10.1007/s11523-014-0329-6 [doi]
AB  - Small molecule inhibitors of epidermal growth factor receptor (EGFR) tyrosine 
      kinase activity, such as erlotinib and gefitinib, revolutionized therapy for 
      non-small cell lung cancer (NSCLC) patients whose tumors harbor activating EGFR 
      mutations. However, mechanisms to overcome the invariable development of acquired 
      resistance to such agents, as well as realizing their full clinical potential 
      within the context of wild-type EGFR (WT-EGFR) disease, remain to be established. 
      Here, the antitumor efficacy of targeted EGFR tyrosine kinase inhibitors (TKIs) 
      and the HSP90 inhibitor ganetespib, alone and in combination, were evaluated in 
      NSCLC. Ganetespib potentiated the efficacy of erlotinib in TKI-sensitive, mutant 
      EGFR-driven NCI-HCC827 xenograft tumors, with combination treatment causing 
      significant tumor regressions. In erlotinib-resistant NCI-H1975 xenografts, 
      concurrent administration of ganetespib overcame erlotinib resistance to 
      significantly improve tumor growth inhibition. Ganetespib co-treatment also 
      significantly enhanced antitumor responses to afatinib in the same model. In 
      WT-EGFR cell lines, ganetespib potently reduced cell viability. In NCI-H1666 
      cells, ganetespib-induced loss of client protein expression, perturbation of 
      oncogenic signaling pathways, and induction of apoptosis translated to robust 
      single-agent activity in vivo. Dual ganetespib/erlotinib therapy induced 
      regressions in NCI-H322 xenograft tumors, indicating that the sensitizing 
      properties of ganetespib for erlotinib were conserved within the WT-EGFR setting. 
      Mechanistically, combined ganetespib/erlotinib exposure stabilized EGFR protein 
      levels in an inactive state and completely abrogated 
      extracellular-signal-regulated kinase (ERK) and AKT signaling activity. Thus, 
      selective HSP90 blockade by ganetespib represents a potentially important 
      complementary strategy to targeted TKI inhibition alone for inducing substantial 
      antitumor responses and overcoming resistance, in both the mutant and WT-EGFR 
      settings.
FAU - Smith, Donald L
AU  - Smith DL
AD  - Synta Pharmaceuticals Corp, 125 Hartwell Ave, Lexington, MA, 02421, USA.
FAU - Acquaviva, Jaime
AU  - Acquaviva J
FAU - Sequeira, Manuel
AU  - Sequeira M
FAU - Jimenez, John-Paul
AU  - Jimenez JP
FAU - Zhang, Chaohua
AU  - Zhang C
FAU - Sang, Jim
AU  - Sang J
FAU - Bates, Richard C
AU  - Bates RC
FAU - Proia, David A
AU  - Proia DA
LA  - eng
PT  - Comparative Study
PT  - Journal Article
DEP - 20140801
PL  - France
TA  - Target Oncol
JT  - Targeted oncology
JID - 101270595
RN  - 0 (HSP90 Heat-Shock Proteins)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (STA 9090)
RN  - 0 (Triazoles)
RN  - EC 2.7.10.1 (EGFR protein, human)
RN  - EC 2.7.10.1 (ErbB Receptors)
SB  - IM
MH  - Animals
MH  - Antineoplastic Combined Chemotherapy Protocols/*pharmacology
MH  - Carcinoma, Non-Small-Cell Lung/*drug therapy/genetics/metabolism/pathology
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Dose-Response Relationship, Drug
MH  - Drug Resistance, Neoplasm
MH  - Drug Synergism
MH  - ErbB Receptors/*antagonists & inhibitors/genetics/metabolism
MH  - Female
MH  - HSP90 Heat-Shock Proteins/*antagonists & inhibitors/metabolism
MH  - Humans
MH  - Lung Neoplasms/*drug therapy/genetics/metabolism/pathology
MH  - Mice, SCID
MH  - *Mutation
MH  - Protein Kinase Inhibitors/*pharmacology
MH  - Signal Transduction/drug effects
MH  - Time Factors
MH  - Triazoles/*pharmacology
MH  - Tumor Burden/drug effects
MH  - Xenograft Model Antitumor Assays
PMC - PMC4457934
EDAT- 2014/08/01 06:00
MHDA- 2016/03/08 06:00
PMCR- 2014/08/01
CRDT- 2014/08/01 06:00
PHST- 2014/05/12 00:00 [received]
PHST- 2014/07/10 00:00 [accepted]
PHST- 2014/08/01 06:00 [entrez]
PHST- 2014/08/01 06:00 [pubmed]
PHST- 2016/03/08 06:00 [medline]
PHST- 2014/08/01 00:00 [pmc-release]
AID - 329 [pii]
AID - 10.1007/s11523-014-0329-6 [doi]
PST - ppublish
SO  - Target Oncol. 2015 Jun;10(2):235-45. doi: 10.1007/s11523-014-0329-6. Epub 2014 
      Aug 1.