A Combination of Approved Antibodies Overcomes Resistance of Lung Cancer to Osimertinib by Blocking Bypass Pathways.

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State: Public
Version: Author's accepted manuscript
Serval ID
serval:BIB_B6471C35DCB6
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
A Combination of Approved Antibodies Overcomes Resistance of Lung Cancer to Osimertinib by Blocking Bypass Pathways.
Journal
Clinical Cancer Research
Author(s)
Romaniello D., Mazzeo L., Mancini M., Marrocco I., Noronha A., Kreitman M., Srivastava S., Ghosh S., Lindzen M., Salame T.M., Onn A., Bar J., Yarden Y.
ISSN
1078-0432 (Print)
ISSN-L
1078-0432
Publication state
Published
Issued date
2018
Peer-reviewed
Oui
Volume
24
Number
22
Pages
5610-5621
Language
english
Abstract
<b>Purpose:</b> Because of emergence of resistance to osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), no targeted treatments are available for patients with lung cancer who lose sensitivity due to new mutations or bypass mechanisms. We examined in animals and <i>in vitro</i> an alternative therapeutic approach making use of antibodies. <b>Experimental Design:</b> An osimertinib-sensitive animal model of lung cancer, which rapidly develops drug resistance, has been employed. To overcome compensatory hyperactivation of ERK, which we previously reported, an anti-EGFR antibody (cetuximab) was combined with other antibodies, as well as with a subtherapeutic dose of osimertinib, and cancer cell apoptosis was assayed. <b>Results:</b> Our animal studies identified a combination of three clinically approved drugs, cetuximab, trastuzumab (an anti-HER2 mAb), and osimertinib (low dose), as an effective and long-lasting treatment that is able to prevent onset of resistance to osimertinib. A continuous schedule of concurrent treatment was sufficient for effective tumor inhibition and for prevention of relapses. Studies employing cultured cells and analyses of tumor extracts indicated that the combination of two mAbs and a subtherapeutic TKI dose sorted EGFR and HER2 for degradation; cooperatively enhanced apoptosis; inhibited activation of ERK; and reduced abundance of several bypass proteins, namely MET, AXL, and HER3. <b>Conclusions:</b> Our <i>in vitro</i> assays and animal studies identified an effective combination of clinically approved drugs that might overcome resistance to irreversible TKIs in clinical settings. The results we present attribute the long-lasting effect of the drug combination to simultaneous blockade of several well-characterized mechanisms of drug resistance. <i>Clin Cancer Res; 24(22); 5610-21. ©2018 AACR</i> <i>See related commentary by Fan and Yu, p. 5499</i> .
Pubmed
Web of science
Open Access
Yes
Create date
17/08/2018 18:27
Last modification date
20/08/2019 15:24
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