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Discovery of drug-resistant and drug-sensitizing mutations in the oncogenic PI3K isoform p110 alpha.

ABSTRACT: p110 alpha (PIK3CA) is the most frequently mutated kinase in human cancer, and numerous drugs targeting this kinase are currently in preclinical development or early-stage clinical trials. Clinical resistance to protein kinase inhibitors frequently results from point mutations that block drug binding; similar mutations in p110 alpha are likely, but currently none have been reported. Using a S. cerevisiae screen against a structurally diverse panel of PI3K inhibitors, we have identified a potential hotspot for resistance mutations (I800), a drug-sensitizing mutation (L814C), and a surprising lack of resistance mutations at the "gatekeeper" residue. Our analysis further reveals that clinical resistance to these drugs may be attenuated by using multitargeted inhibitors that simultaneously inhibit additional PI3K pathway members.

SUBMITTER: Zunder ER

PROVIDER: S-EPMC2720137 | biostudies-literature | 2008 Aug

REPOSITORIES: biostudies-literature

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Discovery of drug-resistant and drug-sensitizing mutations in the oncogenic PI3K isoform p110 alpha.

Zunder Eli R ER Knight Zachary A ZA Houseman Benjamin T BT Apsel Beth B Shokat Kevan M KM

Cancer cell 20080801 2

p110 alpha (PIK3CA) is the most frequently mutated kinase in human cancer, and numerous drugs targeting this kinase are currently in preclinical development or early-stage clinical trials. Clinical resistance to protein kinase inhibitors frequently results from point mutations that block drug binding; similar mutations in p110 alpha are likely, but currently none have been reported. Using a S. cerevisiae screen against a structurally diverse panel of PI3K inhibitors, we have identified a potenti ...[more]

PMID: 18691552

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Oncogenic mutations weaken the interactions that stabilize the p110?-p85? heterodimer in phosphatidylinositol 3-kinase ?.

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Enhanced PI3K p110? signaling confers acquired lapatinib resistance that can be effectively reversed by a p110?-selective PI3K inhibitor.

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| S-EPMC3902650 | biostudies-literature

Oncogenic PI3K mutations are as common as AKT1 and SMO mutations in meningioma.

Project description:BackgroundMeningiomas are the most common primary intracranial tumor in adults. Identification of SMO and AKT1 mutations in meningiomas has raised the possibility of targeted therapies for some patients. The frequency of such mutations in clinical cohorts and the presence of other actionable mutations in meningiomas are important to define.MethodsWe used high-resolution array-comparative genomic hybridization to prospectively characterize copy-number changes in 150 meningiomas and then characterized these samples for mutations in AKT1, KLF4, NF2, PIK3CA, SMO, and TRAF7.ResultsSimilar to prior reports, we identified AKT1 and SMO mutations in a subset of non-NF2-mutant meningiomas (ie, ∼9% and ∼6%, respectively). Notably, we detected oncogenic mutations in PIK3CA in ∼7% of non-NF2-mutant meningiomas. AKT1, SMO, and PIK3CA mutations were mutually exclusive. AKT1, KLF4, and PIK3CA mutations often co-occurred with mutations in TRAF7. PIK3CA-mutant meningiomas showed limited chromosomal instability and were enriched in the skull base.ConclusionThis work identifies PI3K signaling as an important target for precision medicine trials in meningioma patients.

| S-EPMC4827048 | biostudies-literature

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