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Nf1-Mutant Tumors Undergo Transcriptome and Kinome Remodeling after Inhibition of either mTOR or MEK.


ABSTRACT: Loss of the tumor suppressor NF1 leads to activation of RAS effector pathways, which are therapeutically targeted by inhibition of mTOR (mTORi) or MEK (MEKi). However, therapeutic inhibition of RAS effectors leads to the development of drug resistance and ultimately disease progression. To investigate molecular signatures in the context of NF1 loss and subsequent acquired drug resistance, we analyzed the exomes, transcriptomes, and kinomes of Nf1-mutant mouse tumor cell lines and derivatives of these lines that acquired resistance to either MEKi or mTORi. Biochemical comparisons of this unique panel of tumor cells, all of which arose in Nf1+/- mice, indicate that loss of heterozygosity of Nf1 as an initial genetic event does not confer a common biochemical signature or response to kinase inhibition. Although acquired drug resistance by Nf1-mutant tumor cells was accompanied by altered kinomes and irreversibly altered transcriptomes, functionally in multiple Nf1-mutant tumor cell lines, MEKi resistance was a stable phenotype, in contrast to mTORi resistance, which was reversible. Collectively, these findings demonstrate that Nf1-mutant tumors represent a heterogeneous group biochemically and undergo broader remodeling of kinome activity and gene expression in response to targeted kinase inhibition.

SUBMITTER: Pucciarelli D 

PROVIDER: S-EPMC7907257 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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<i>Nf1</i>-Mutant Tumors Undergo Transcriptome and Kinome Remodeling after Inhibition of either mTOR or MEK.

Pucciarelli Daniela D   Angus Steven P SP   Huang Benjamin B   Zhang Chi C   Nakaoka Hiroki J HJ   Krishnamurthi Ganesh G   Bandyopadhyay Sourav S   Clapp D Wade DW   Shannon Kevin K   Johnson Gary L GL   Nakamura Jean L JL  

Molecular cancer therapeutics 20200826 11


Loss of the tumor suppressor <i>NF1</i> leads to activation of RAS effector pathways, which are therapeutically targeted by inhibition of mTOR (mTORi) or MEK (MEKi). However, therapeutic inhibition of RAS effectors leads to the development of drug resistance and ultimately disease progression. To investigate molecular signatures in the context of <i>NF1</i> loss and subsequent acquired drug resistance, we analyzed the exomes, transcriptomes, and kinomes of <i>Nf1</i>-mutant mouse tumor cell line  ...[more]

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