PMID- 19117999
OWN - NLM
STAT- MEDLINE
DCOM- 20090130
LR  - 20240328
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 69
IP  - 1
DP  - 2009 Jan 1
TI  - The mechanisms of differential sensitivity to an insulin-like growth factor-1 
      receptor inhibitor (BMS-536924) and rationale for combining with EGFR/HER2 
      inhibitors.
PG  - 161-70
LID - 10.1158/0008-5472.CAN-08-0835 [doi]
AB  - Overexpression and enhanced activity of insulin-like growth factor-I receptor 
      (IGF-IR) in diverse tumor types make it an attractive target for cancer therapy. 
      BMS-536924 is a potent small molecule inhibitor of IGF-IR, which shows antitumor 
      activity in multiple tumor models, including sarcoma. To facilitate the 
      development of IGF-IR inhibitors as cancer therapy, identification of biomarkers 
      for selecting patients most likely to derive clinical benefit is needed. To do 
      so, 28 sarcoma and neuroblastoma cell lines were screened for in vitro response 
      to BMS-536924 to identify sensitive and resistant cell lines. Notably, Ewing's 
      sarcoma, rhabdomyosarcoma, and neuroblastoma are more responsive to BMS-536924, 
      suggesting these specific subtypes may represent potential targeted patient 
      subpopulations for the IGF-IR inhibitor. Gene expression and protein profiling 
      were performed on these cell lines, and candidate biomarkers correlating with 
      intrinsic and/or acquired resistance to BMS-536924 were identified. IGF-I, 
      IGF-II, and IGF-IR were highly expressed in sensitive cell lines, whereas IGFBP-3 
      and IGFBP-6 were highly expressed in resistant lines. Overexpression of epidermal 
      growth factor receptor (EGFR) and its ligands in resistant cell lines may 
      represent one possible resistance mechanism by the adaptation of 
      IGF-IR-independent growth using alternative signaling pathways. Based on 
      cross-talk between IGF-IR and EGFR pathways, combination studies to target both 
      pathways were performed, and enhanced inhibitory activities were observed. These 
      results provide a strategy for testing combinations of IGF-IR inhibitors with 
      other targeted therapies in clinical studies to achieve improved patient 
      outcomes. Further exploration of mechanisms for intrinsic and acquired drug 
      resistance by these preclinical studies may lead to more rationally designed 
      drugs that target multiple pathways for enhanced antitumor efficacy.
FAU - Huang, Fei
AU  - Huang F
AD  - Bristol-Myers Squibb Company, Princeton, NJ 08543, USA. fei.huang@bms.com
FAU - Greer, Ann
AU  - Greer A
FAU - Hurlburt, Warren
AU  - Hurlburt W
FAU - Han, Xia
AU  - Han X
FAU - Hafezi, Rameh
AU  - Hafezi R
FAU - Wittenberg, Gayle M
AU  - Wittenberg GM
FAU - Reeves, Karen
AU  - Reeves K
FAU - Chen, Jiwen
AU  - Chen J
FAU - Robinson, Douglas
AU  - Robinson D
FAU - Li, Aixin
AU  - Li A
FAU - Lee, Francis Y
AU  - Lee FY
FAU - Gottardis, Marco M
AU  - Gottardis MM
FAU - Clark, Edwin
AU  - Clark E
FAU - Helman, Lee
AU  - Helman L
FAU - Attar, Ricardo M
AU  - Attar RM
FAU - Dongre, Ashok
AU  - Dongre A
FAU - Carboni, Joan M
AU  - Carboni JM
LA  - eng
GR  - Z01 SC006891/ImNIH/Intramural NIH HHS/United States
GR  - ZIA SC006891/ImNIH/Intramural NIH HHS/United States
GR  - Z01 SC006891-19/ImNIH/Intramural NIH HHS/United States
GR  - ZIA BC010566/ImNIH/Intramural NIH HHS/United States
GR  - Z01 SC006892/ImNIH/Intramural NIH HHS/United States
PT  - Journal Article
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (BMS 536924)
RN  - 0 (Benzimidazoles)
RN  - 0 (Pyridones)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
RN  - EC 2.7.10.1 (Receptor, IGF Type 1)
SB  - IM
MH  - Antineoplastic Combined Chemotherapy Protocols/*pharmacology
MH  - Apoptosis/drug effects
MH  - Benzimidazoles/*pharmacology
MH  - Cell Growth Processes/drug effects
MH  - Cell Line, Tumor
MH  - Drug Resistance, Neoplasm
MH  - Drug Synergism
MH  - ErbB Receptors/*antagonists & inhibitors/metabolism
MH  - Gene Expression/drug effects
MH  - Gene Expression Profiling
MH  - Humans
MH  - Neuroblastoma/*drug therapy/genetics/metabolism/pathology
MH  - Pyridones/*pharmacology
MH  - Receptor, ErbB-2/*antagonists & inhibitors/metabolism
MH  - Receptor, IGF Type 1/*antagonists & inhibitors
MH  - Sarcoma/*drug therapy/genetics/metabolism/pathology
PMC - PMC7255694
MID - NIHMS1583519
COIS- Disclosure of Potential Conflicts of Interest No potential conflicts of interest 
      were disclosed.
EDAT- 2009/01/02 09:00
MHDA- 2009/01/31 09:00
PMCR- 2020/05/28
CRDT- 2009/01/02 09:00
PHST- 2009/01/02 09:00 [entrez]
PHST- 2009/01/02 09:00 [pubmed]
PHST- 2009/01/31 09:00 [medline]
PHST- 2020/05/28 00:00 [pmc-release]
AID - 69/1/161 [pii]
AID - 10.1158/0008-5472.CAN-08-0835 [doi]
PST - ppublish
SO  - Cancer Res. 2009 Jan 1;69(1):161-70. doi: 10.1158/0008-5472.CAN-08-0835.