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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