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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 of p110? isoform of PI 3-kinase upregulate its protein kinase activity.

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2023-11-01 | GSE242387 | GEO

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Isoform-selective induction of human p110? PI3K expression by TNF?: identification of a new and inducible PIK3CD promoter.

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

Project description:BACKGROUND:Meningiomas 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. METHODS:We 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. RESULTS:Similar 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. CONCLUSION:This work identifies PI3K signaling as an important target for precision medicine trials in meningioma patients.

| S-EPMC4827048 | biostudies-literature

Oncogenic PI3K mutations lead to NF-kB-dependent cytokine expression following growth

Project description:While growth factor-independent signaling and proliferation are well-established hallmarks of cancer, little is known regarding growth factor-independent changes in gene expression which occur downstream from oncogenes. The PI3K pathway is one of the most commonly misregulated signaling pathways in human cancers. Here, MCF10A cells expressing the two most common PI3K mutations, PIK3CA E545K and H1047R, were used to identify the repertoire of genes altered by oncogenic PI3K mutations following growth factor deprivation. This gene set most closely correlated with gene signatures from claudin-low and basal-like breast tumors, and categorical enrichment analyses suggested that NF-kB target genes were dramatically upregulated by these mutations. An IKKb inhibitor was used to identify the subset of PI3K-driven genes that is NF-kB dependent. Interestingly, virtually all of these NF-kB dependent genes were secreted proteins, suggesting a paracrine role for this gene set. Among these genes was IL-6, a cytokine frequently expressed in tumors which plays a critical role in generating a tumor-promoting microenvironment. Consistent with this, conditioned media from cells expressing the E545K or H1047R mutations led to increased STAT3 activation in recipient THP-1 monocytes or normal epithelial cells in a NF-kB and IL-6-dependent manner. Together, these data describe a PI3K-driven, NF-kB-dependent gene expression profile which may play a critical role in promoting a microenvironment amenable to tumor progression. 39 normal cell lines vs treated cell lines for micorarray analysis

| S-ECPF-GEOD-33403 | biostudies-other

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