Increased synthesis of MCL-1 protein underlies initial survival of EGFR mutant lung cancer to EGFR inhibitors and provides a novel drug target
EGFR inhibitors (EGFRi) are effective against mutant lung cancers. The efficacy of these drugs however is mitigated by the outgrowth of resistant cells, most often driven by a secondary acquired mutation in EGFR, We recently demonstrated that can arise during treatment (Hata et al., 2016); it follow...
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Published in | Clinical cancer research Vol. 24; no. 22; pp. 5658 - 5672 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
15.11.2018
|
Online Access | Get full text |
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Summary: | EGFR inhibitors (EGFRi) are effective against
mutant lung cancers. The efficacy of these drugs however is mitigated by the outgrowth of resistant cells, most often driven by a secondary acquired mutation in EGFR,
We recently demonstrated that
can arise
during treatment (Hata et al.,
2016); it follows that one potential therapeutic strategy to thwart resistance would be identifying and eliminating these cells (referred to as drug tolerant cells (DTCs)) prior to acquiring secondary mutations like
Experimental Design: We have developed DTCs to EGFRi in
mutant lung cancer cell lines. Subsequent analyses of DTCs included RNA-seq, high-content microscopy, and protein translational assays. Based on these results, we tested the ability of MCL-1 BH3 mimetics to combine with EGFR inhibitors to eliminate DTCs and shrink
mutant lung cancer tumors
Results: We demonstrate surviving
mutant lung cancers upregulate the anti-apoptotic protein MCL-1 in response to short-term EGFRi treatment. Mechanistically, DTCs undergo a protein biosynthesis enrichment resulting in increased mTORC1-mediated mRNA translation of MCL-1, revealing a novel mechanism in which lung cancer cells adapt to short-term pressures of apoptosis-inducing kinase inhibitors. Moreover, MCL-1 is a key molecule governing the emergence of early
mutant DTCs to EGFRi and we demonstrate it can be effectively co-targeted with clinically-emerging MCL-1 inhibitors both
and
Conclusions: Altogether, these data reveal that this novel therapeutic combination may delay the acquisition of secondary mutations, therefore prolonging therapy efficacy. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1078-0432 1557-3265 |
DOI: | 10.1158/1078-0432.ccr-18-0304 |