ERBB3-independent activation of the PI3K pathway in EGFR-mutant lung adenocarcinomas Journal Article


Authors: Song, X. L.; Fan, P. D.; Bantikassegn, A.; Guha, U.; Threadgill, D. W.; Varmus, H.; Politi, K.
Article Title: ERBB3-independent activation of the PI3K pathway in EGFR-mutant lung adenocarcinomas
Abstract: ERBB3, a member of the EGFR family of receptor tyrosine kinases, has been implicated in activation of the PI3K pathway in human lung adenocarcinomas driven by EGFR mutations. We investigated the contribution of ERBB3 to the initiation, progression, and therapeutic response of EGFR-induced lung adenocarcinomas using tetracycline-and tamoxifen-inducible transgenic mouse models. Deletion of Erbb3 at the time of induction of mutant EGFR had no effect on tumorigenesis, demonstrating that ERBB3 is not required to initiate tumorigenesis. Tumors that developed in the absence of ERBB3 remained sensitive to EGFR tyrosine kinase inhibitors and retained activation of the PI3KAKT pathway. Interestingly, acute loss of Erbb3 suppressed further growth of established EGFRL858R-mediated lung tumors. Four weeks after deletion of Erbb3, the tumors exhibited phosphorylation of EGFR, of the adaptor proteins GAB1 and GAB2, and of the downstream signaling molecules AKT and ERK, suggesting that alternative signaling pathways could compensate for loss of Erbb3. Similar to our observations with mouse tumors, we found that GAB adaptor proteins play a role in ERBB3-independent activation of the PI3K pathway bymutant EGFR in EGFR-mutant human cell lines. Finally, in such cell lines, increased levels of phosphorylation of ERBB2 or MET were associated with reduced sensitivity to acute loss of ERBB3, suggesting remarkable plasticity in the signaling pathways regulated by mutant EGFR with important therapeutic implications.
Keywords: erlotinib; gefitinib; mutations; phosphatidylinositol 3-kinase; epidermal-growth-factor; factor receptor; kinase domain; met amplification; erbb3; cancer
Journal Title: Cancer Research
Volume: 75
Issue: 6
ISSN: 0008-5472
Publisher: American Association for Cancer Research  
Date Published: 2015-03-15
Start Page: 1035
End Page: 1045
Language: English
ACCESSION: WOS:000351941400013
DOI: 10.1158/0008-5472.can-13-1625
PROVIDER: wos
PMCID: PMC4400867
PUBMED: 25596284
Notes: Article -- Source: Wos
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MSK Authors
  1. Udayan Guha
    4 Guha
  2. Katerina A Politi
    23 Politi
  3. Pang-Dian Fan
    13 Fan
  4. Harold Varmus
    96 Varmus