title: Naturally occurring neomorphic PIK3R1 mutations activate the MAPK pathway, dictating therapeutic response to MAPK pathway inhibitors.
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.
authors.affiliation: Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: wcheung@mdanderson.org.
authors.forename: Lydia W T
authors.initials: LW
authors.lastname: Cheung
authors.affiliation: Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Shuangxing
authors.initials: S
authors.lastname: Yu
authors.affiliation: Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Dong
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Patrick K S
authors.initials: PK
authors.lastname: Ng
authors.affiliation: Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Physiology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand.
authors.forename: Nattapon
authors.initials: N
authors.lastname: Panupinthu
authors.affiliation: Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Shreya
authors.initials: S
authors.lastname: Mitra
authors.affiliation: Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Zhenlin
authors.initials: Z
authors.lastname: Ju
authors.affiliation: Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Yu
authors.affiliation: Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Han
authors.initials: H
authors.lastname: Liang
authors.affiliation: Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Hawke
authors.affiliation: Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Yiling
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Russell R
authors.initials: RR
authors.lastname: Broaddus
authors.affiliation: Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002467:Cell Nucleus / Q000378:metabolism; D058543:Class Ia Phosphatidylinositol 3-Kinase; D004789:Enzyme Activation; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D021381:Protein Transport
chemical_list: D000970:Antineoplastic Agents; D058543:Class Ia Phosphatidylinositol 3-Kinase; D019869:Phosphatidylinositol 3-Kinases; C588001:PIK3R1 protein, human