PMID- 28723928
OWN - NLM
STAT- MEDLINE
DCOM- 20170926
LR  - 20181202
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 12
IP  - 7
DP  - 2017
TI  - ErbB activation signatures as potential biomarkers for anti-ErbB3 treatment in 
      HNSCC.
PG  - e0181356
LID - 10.1371/journal.pone.0181356 [doi]
LID - e0181356
AB  - Head and neck squamous cell carcinoma (HNSCC) accounts for 3-5% of all tumor 
      types and remains an unmet medical need with only two targeted therapies approved 
      to date. ErbB3 (HER3), the kinase-impaired member of the EGFR/ErbB family, has 
      been implicated as a disease driver in a number of solid tumors, including a 
      subset of HNSCC. Here we show that the molecular components required for ErbB3 
      activation, including its ligand neuregulin-1 (NRG1), are highly prevalent in 
      HNSCC and that HER2, but not EGFR, is the major activating ErbB3 kinase partner. 
      We demonstrate that cetuximab treatment primarily inhibits the ERK signaling 
      pathway and KTN3379, an anti-ErbB3 monoclonal antibody, inhibits the AKT 
      signaling pathway, and that dual ErbB receptor inhibition results in enhanced 
      anti-tumor activity in HNSCC models. Surprisingly, we found that while NRG1 is 
      required for ErbB3 activation, it was not sufficient to fully predict for KTN3379 
      activity. An evaluation of HNSCC patient samples demonstrated that NRG1 
      expression was significantly associated with expression of the EGFR ligands 
      amphiregulin (AREG) and transforming growth factor alpha (TGFalpha). Furthermore, 
      NRG1-positive HNSCC cell lines that secreted high levels of AREG and TGFalpha or 
      contained high levels of EGFR homodimers (H11D) demonstrated a better response to 
      KTN3379. Although ErbB3 and EGFR activation are uncoupled at the receptor level, 
      their respective signaling pathways are linked through co-expression of their 
      respective ligands. We propose that NRG1 expression and EGFR activation 
      signatures may enrich for improved efficacy of anti-ErbB3 therapeutic mAb 
      approaches when combined with EGFR-targeting therapies in HNSCC.
FAU - Alvarado, Diego
AU  - Alvarado D
AUID- ORCID: 0000-0002-5878-1730
AD  - Kolltan Pharmaceuticals., New Haven, Connecticut, United States of America.
FAU - Ligon, Gwenda F
AU  - Ligon GF
AD  - Kolltan Pharmaceuticals., New Haven, Connecticut, United States of America.
FAU - Lillquist, Jay S
AU  - Lillquist JS
AD  - Kolltan Pharmaceuticals., New Haven, Connecticut, United States of America.
FAU - Seibel, Scott B
AU  - Seibel SB
AD  - Kolltan Pharmaceuticals., New Haven, Connecticut, United States of America.
FAU - Wallweber, Gerald
AU  - Wallweber G
AD  - Monogram Biosciences, Laboratory Corporation of America(R) Holdings, South San 
      Francisco, California, United States of America.
FAU - Neumeister, Veronique M
AU  - Neumeister VM
AD  - Yale Pathology Tissue Services, Yale University, New Haven, Connecticut, United 
      States of America.
FAU - Rimm, David L
AU  - Rimm DL
AD  - Yale Pathology Tissue Services, Yale University, New Haven, Connecticut, United 
      States of America.
FAU - McMahon, Gerald
AU  - McMahon G
AD  - Kolltan Pharmaceuticals., New Haven, Connecticut, United States of America.
FAU - LaVallee, Theresa M
AU  - LaVallee TM
AD  - Kolltan Pharmaceuticals., New Haven, Connecticut, United States of America.
LA  - eng
PT  - Journal Article
DEP - 20170719
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (Neuregulin-1)
RN  - EC 2.7.10.1 (EGFR protein, human)
RN  - EC 2.7.10.1 (ERBB2 protein, human)
RN  - EC 2.7.10.1 (ERBB3 protein, human)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
RN  - EC 2.7.10.1 (Receptor, ErbB-3)
RN  - PQX0D8J21J (Cetuximab)
SB  - IM
MH  - Antineoplastic Agents/*pharmacology/therapeutic use
MH  - Biomarkers, Tumor/metabolism
MH  - Carcinoma, Squamous Cell/drug therapy/*metabolism/pathology
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Cetuximab/*pharmacology/therapeutic use
MH  - ErbB Receptors/*metabolism
MH  - Head and Neck Neoplasms/drug therapy/*metabolism/pathology
MH  - Humans
MH  - Neuregulin-1/metabolism
MH  - Receptor, ErbB-2/metabolism
MH  - Receptor, ErbB-3/*metabolism
MH  - Signal Transduction/drug effects
PMC - PMC5517012
COIS- Competing Interests: DA, GFL, JSL, SBS AND TML are full time employees of Celldex 
      Therapeutics (http://www.celldex.com/), which acquired Kolltan Pharmaceuticals in 
      2016. DA and TML are inventors in patent applications WO/2016/168634A1 and 
      WO/2016/040622A1. The anti-ErbB3 mAb KTN3379 (now CDX-3379) is in clinical 
      development at the time of this submission. GW is a full time employee of 
      Monogram Biosciences. This does not alter our adherence to PLOS ONE policies on 
      sharing data and materials.
EDAT- 2017/07/21 06:00
MHDA- 2017/09/28 06:00
PMCR- 2017/07/19
CRDT- 2017/07/21 06:00
PHST- 2017/01/11 00:00 [received]
PHST- 2017/06/29 00:00 [accepted]
PHST- 2017/07/21 06:00 [entrez]
PHST- 2017/07/21 06:00 [pubmed]
PHST- 2017/09/28 06:00 [medline]
PHST- 2017/07/19 00:00 [pmc-release]
AID - PONE-D-17-01411 [pii]
AID - 10.1371/journal.pone.0181356 [doi]
PST - epublish
SO  - PLoS One. 2017 Jul 19;12(7):e0181356. doi: 10.1371/journal.pone.0181356. 
      eCollection 2017.