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

Lydia W T Cheung, Shuangxing Yu, Dong Zhang, Jie Li, Patrick K S Ng, Nattapon Panupinthu, Shreya Mitra, Zhenlin Ju, Qinghua Yu, Han Liang, David H. Hawke, Yiling Lu, Russell R. Broaddus, Gordon Mills

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)479-494
Number of pages16
JournalCancer Cell
Volume26
Issue number4
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

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Mutation
MAP Kinase Signaling System
Mitogen-Activated Protein Kinase Kinases
Therapeutics
Phosphatidylinositol 3-Kinases
Neoplasms
Phosphorylation

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Naturally occurring neomorphic PIK3R1 mutations activate the MAPK pathway, dictating therapeutic response to MAPK pathway inhibitors. / Cheung, Lydia W T; Yu, Shuangxing; Zhang, Dong; Li, Jie; Ng, Patrick K S; Panupinthu, Nattapon; Mitra, Shreya; Ju, Zhenlin; Yu, Qinghua; Liang, Han; Hawke, David H.; Lu, Yiling; Broaddus, Russell R.; Mills, Gordon.

In: Cancer Cell, Vol. 26, No. 4, 01.01.2014, p. 479-494.

Research output: Contribution to journalArticle

Cheung, LWT, Yu, S, Zhang, D, Li, J, Ng, PKS, Panupinthu, N, Mitra, S, Ju, Z, Yu, Q, Liang, H, Hawke, DH, Lu, Y, Broaddus, RR & Mills, G 2014, 'Naturally occurring neomorphic PIK3R1 mutations activate the MAPK pathway, dictating therapeutic response to MAPK pathway inhibitors', Cancer Cell, vol. 26, no. 4, pp. 479-494. https://doi.org/10.1016/j.ccell.2014.08.017
Cheung, Lydia W T ; Yu, Shuangxing ; Zhang, Dong ; Li, Jie ; Ng, Patrick K S ; Panupinthu, Nattapon ; Mitra, Shreya ; Ju, Zhenlin ; Yu, Qinghua ; Liang, Han ; Hawke, David H. ; Lu, Yiling ; Broaddus, Russell R. ; Mills, Gordon. / Naturally occurring neomorphic PIK3R1 mutations activate the MAPK pathway, dictating therapeutic response to MAPK pathway inhibitors. In: Cancer Cell. 2014 ; Vol. 26, No. 4. pp. 479-494.
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