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Article: Naturally occurring neomorphic PIK3R1 mutations activate the MAPK pathway, dictating therapeutic response to MAPK pathway inhibitors

TitleNaturally occurring neomorphic PIK3R1 mutations activate the MAPK pathway, dictating therapeutic response to MAPK pathway inhibitors
Authors
Issue Date2014
Citation
Cancer Cell, 2014, v. 26, n. 4, p. 479-494 How to Cite?
Abstract© 2014 Elsevier Inc. PIK3R1 (p85α regulatory subunit of PI3K) is frequently mutated across cancer lineages. Herein, we demonstrate that the most common recurrent PIK3R1 mutation PIK3R1R348* and a nearby mutation PIK3R1L370fs, in contrast to wild-type and mutations in other regions of PIK3R1, confers an unexpected sensitivity to MEK and JNK inhibitors invitro and invivo. Consistent with the response to inhibitors, PIK3R1R348* and PIK3R1L370fs unexpectedly increase JNK and ERK phosphorylation. Surprisingly, p85α R348* and L370fs localize to the nucleus where the mutants provide a scaffold for multiple JNK pathway components facilitating nuclear JNK pathway activation. Our findings uncover an unexpected neomorphic role for PIK3R1R348* and neighboring truncation mutations in cellular signaling, providing a rationale for therapeutic targeting of these mutant tumors.
Persistent Identifierhttp://hdl.handle.net/10722/225062
ISSN
2015 Impact Factor: 23.214
2015 SCImago Journal Rankings: 13.922

 

DC FieldValueLanguage
dc.contributor.authorCheung, LydiaW T.-
dc.contributor.authorYu, Shuangxing-
dc.contributor.authorZhang, Dong-
dc.contributor.authorLi, Jie-
dc.contributor.authorNg, PatrickK S.-
dc.contributor.authorPanupinthu, Nattapon-
dc.contributor.authorMitra, Shreya-
dc.contributor.authorJu, Zhenlin-
dc.contributor.authorYu, Qinghua-
dc.contributor.authorLiang, Han-
dc.contributor.authorHawke, DavidH-
dc.contributor.authorLu, Yiling-
dc.contributor.authorBroaddus, RussellR-
dc.contributor.authorMills, GordonB-
dc.date.accessioned2016-04-18T11:16:40Z-
dc.date.available2016-04-18T11:16:40Z-
dc.date.issued2014-
dc.identifier.citationCancer Cell, 2014, v. 26, n. 4, p. 479-494-
dc.identifier.issn1535-6108-
dc.identifier.urihttp://hdl.handle.net/10722/225062-
dc.description.abstract© 2014 Elsevier Inc. PIK3R1 (p85α regulatory subunit of PI3K) is frequently mutated across cancer lineages. Herein, we demonstrate that the most common recurrent PIK3R1 mutation PIK3R1R348* and a nearby mutation PIK3R1L370fs, in contrast to wild-type and mutations in other regions of PIK3R1, confers an unexpected sensitivity to MEK and JNK inhibitors invitro and invivo. Consistent with the response to inhibitors, PIK3R1R348* and PIK3R1L370fs unexpectedly increase JNK and ERK phosphorylation. Surprisingly, p85α R348* and L370fs localize to the nucleus where the mutants provide a scaffold for multiple JNK pathway components facilitating nuclear JNK pathway activation. Our findings uncover an unexpected neomorphic role for PIK3R1R348* and neighboring truncation mutations in cellular signaling, providing a rationale for therapeutic targeting of these mutant tumors.-
dc.languageeng-
dc.relation.ispartofCancer Cell-
dc.titleNaturally occurring neomorphic PIK3R1 mutations activate the MAPK pathway, dictating therapeutic response to MAPK pathway inhibitors-
dc.typeArticle-
dc.description.natureLink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.ccell.2014.08.017-
dc.identifier.scopuseid_2-s2.0-84907967403-
dc.identifier.volume26-
dc.identifier.issue4-
dc.identifier.spage479-
dc.identifier.epage494-
dc.identifier.eissn1878-3686-
dc.identifier.f1000719709847-

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