What question did this study set out to answer?

To elucidate how co-occurring EIF1AX and RAS mutations cooperate to drive advanced thyroid tumorigenesis and identify downstream targetable vulnerabilities.

October 10, 2018Cancer DiscoveryOpen Access

EIF1AX and RAS Mutations Cooperate to Drive Thyroid Tumorigenesis through ATF4 and c-MYC

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Authors

GKGnana P. KrishnamoorthyMemorial Sloan Kettering Cancer Center NDNatalie R. DavidsonTel Aviv University SLSteven D. LeachDartmouth College

Discussion

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Implication

Preclinical study reveals cooperative oncogenic mechanisms in advanced thyroid cancer models, highlighting therapeutic vulnerabilities to mTOR, MEK, and BRD4 inhibitors.

Key Points

To elucidate how co-occurring EIF1AX and RAS mutations cooperate to drive advanced thyroid tumorigenesis and identify downstream targetable vulnerabilities.
Assessed tumor formation driven by EIF1AX and RAS mutations using mouse models and isogenic thyroid cell lines.
Characterized the molecular impact of the recurrent EIF1AX-A113splice variant on 43S preinitiation complex stability, EIF2α phosphorylation, and translation initiation.
Analyzed downstream metabolic and transcriptional pathways regulated by ATF4 and c-MYC, including amino acid transport and mTOR kinase sensitivity.
EIF1AX mutations, particularly the EIF1AX-A113splice variant, strongly co-occurred with RAS in advanced thyroid cancers and cooperatively accelerated tumorigenesis in vivo and in vitro.
EIF1AX-A113splice stabilized the translation preinitiation complex and induced ATF4, which suppressed EIF2α phosphorylation to drive a general increase in protein synthesis.
ATF4 and RAS-stabilized c-MYC jointly upregulated amino acid transporters and enhanced mTOR sensitivity to amino acids, conferring therapeutic sensitivity to MEK, BRD4, and mTOR kinase inhibitors.

Cite This Study

Krishnamoorthy et al. (2018) studied this question.

synapsesocial.com/papers/69dd5db27dbdc4ad1440c686 https://doi.org/10.1158/2159-8290.cd-18-0606

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October 10, 2018Cancer DiscoveryOpen Access

EIF1AX and RAS Mutations Cooperate to Drive Thyroid Tumorigenesis through ATF4 and c-MYC

View Full Paper

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Bookmark

Authors

GKGnana P. KrishnamoorthyMemorial Sloan Kettering Cancer Center NDNatalie R. DavidsonTel Aviv University SLSteven D. LeachDartmouth College

Discussion

Member takes

Implication

Preclinical study reveals cooperative oncogenic mechanisms in advanced thyroid cancer models, highlighting therapeutic vulnerabilities to mTOR, MEK, and BRD4 inhibitors.

Key Points

To elucidate how co-occurring EIF1AX and RAS mutations cooperate to drive advanced thyroid tumorigenesis and identify downstream targetable vulnerabilities.
Assessed tumor formation driven by EIF1AX and RAS mutations using mouse models and isogenic thyroid cell lines.
Characterized the molecular impact of the recurrent EIF1AX-A113splice variant on 43S preinitiation complex stability, EIF2α phosphorylation, and translation initiation.
Analyzed downstream metabolic and transcriptional pathways regulated by ATF4 and c-MYC, including amino acid transport and mTOR kinase sensitivity.
EIF1AX mutations, particularly the EIF1AX-A113splice variant, strongly co-occurred with RAS in advanced thyroid cancers and cooperatively accelerated tumorigenesis in vivo and in vitro.
EIF1AX-A113splice stabilized the translation preinitiation complex and induced ATF4, which suppressed EIF2α phosphorylation to drive a general increase in protein synthesis.
ATF4 and RAS-stabilized c-MYC jointly upregulated amino acid transporters and enhanced mTOR sensitivity to amino acids, conferring therapeutic sensitivity to MEK, BRD4, and mTOR kinase inhibitors.

Cite This Study

Krishnamoorthy et al. (2018) studied this question.

synapsesocial.com/papers/69dd5db27dbdc4ad1440c686 https://doi.org/10.1158/2159-8290.cd-18-0606

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