論文 - 詳細
| RRC ID | 45333 |
|---|---|
| 著者 | Cheung LW, Yu S, Zhang D, Li J, Ng PK, Panupinthu N, Mitra S, Ju Z, Yu Q, Liang H, Hawke DH, Lu Y, Broaddus RR, Mills GB. |
| タイトル | Naturally occurring neomorphic PIK3R1 mutations activate the MAPK pathway, dictating therapeutic response to MAPK pathway inhibitors. |
| ジャーナル | Cancer Cell |
| Abstract |
PIK3R1 (p85α regulatory subunit of PI3K) is frequently mutated across cancer lineages. Herein, we demonstrate that the most common recurrent PIK3R1 mutation PIK3R1(R348∗) and a nearby mutation PIK3R1(L370fs), in contrast to wild-type and mutations in other regions of PIK3R1, confers an unexpected sensitivity to MEK and JNK inhibitors in vitro and in vivo. Consistent with the response to inhibitors, PIK3R1(R348∗) and PIK3R1(L370fs) 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 PIK3R1(R348∗) and neighboring truncation mutations in cellular signaling, providing a rationale for therapeutic targeting of these mutant tumors. |
| 巻・号 | 26(4) |
| ページ | 479-94 |
| 公開日 | 2014-10-13 |
| DOI | 10.1016/j.ccell.2014.08.017 |
| PII | S1535-6108(14)00349-3 |
| PMID | 25284480 |
| PMC | PMC4198486 |
| MeSH | Antineoplastic Agents / pharmacology Antineoplastic Agents / therapeutic use Cell Nucleus / metabolism Class Ia Phosphatidylinositol 3-Kinase Enzyme Activation Humans MAP Kinase Signaling System / drug effects* Mutation* Phosphatidylinositol 3-Kinases / genetics* Phosphatidylinositol 3-Kinases / metabolism Phosphorylation Protein Transport |
| IF | 26.602 |
| 引用数 | 48 |
| WOS 分野 | ONCOLOGY CELL BIOLOGY |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 10 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.2 |
| リソース情報 | |
| ヒト・動物細胞 | OVK18(RCB1903) |