<i>PIK3CA</i> Mutations and Copy Number Gains in Human Lung Cancers

Yamamoto, Hiromasa; Shigematsu, Hisayuki; Nomura, Masatoshi; Lockwood, William W.; Sato, Mitsuo; Okumura, Naoki; Soh, Junichi; Suzuki, Makoto; Wistuba, Ignacio I.; Fong, Kwun M.; Lee, Huei; Toyooka, Shinichi; Date, Hiroshi; Lam, Wan L.; Minna, John D.; Gazdar, Adi F.

doi:10.1158/0008-5472.can-07-5084

Cited by 384 publications

(344 citation statements)

References 38 publications

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“…It has been recently reported that, albeit rarely, EGFR and PIK3CA mutations can coexist in human tumors (30), and that activation of the PI3K/AKT signaling pathway can circumvent the effect of EGFR tyrosine kinase inhibitors. To verify whether we could recapitulate this phenomenon in our cellular model as well, we generated double KI clones (DKI) carrying both the PIK3CA (H1047R) and EGFR (delE746-A750) mutations.…”

Section: Knock-in Cells Display Drug Responses Resembling Those Of Tumentioning

confidence: 99%

Replacement of normal with mutant alleles in the genome of normal human cells unveils mutation-specific drug responses

Nicolantonio

Arena

Gallicchio

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

124

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Mutations in oncogenes and tumor suppressor genes are responsible for tumorigenesis and represent favored therapeutic targets in oncology. We exploited homologous recombination to knock-in individual cancer mutations in the genome of nontransformed human cells. Sequential introduction of multiple mutations was also achieved, demonstrating the potential of this strategy to construct tumor progression models. Knock-in cells displayed allele-specific activation of signaling pathways and mutation-specific phenotypes different from those obtainable by ectopic oncogene expression. Profiling of a library of pharmacological agents on the mutated cells showed striking sensitivity or resistance phenotypes to pathway-targeted drugs, often matching those of tumor cells carrying equivalent cancer mutations. Thus, knock-in of single or multiple cancer alleles provides a pharmacogenomic platform for the rational design of targeted therapies.cancer mutation ͉ oncogene addiction ͉ pharmacogenomic ͉ targeted therapies ͉ tumor progression model T he construction of model systems that accurately recapitulate the genetic alterations present in human cancer is a prerequisite to understand the cellular properties imparted by the mutated alleles and to identify genotype and tumor-specific pharmacological responses. In this regard, mammalian cell lines have been widely used as model systems to functionally characterize cancer alleles carrying point mutations and to develop and validate anticancer drugs. These models typically involve the ectopic expression (by means of plasmid transfection or viral infection) of mutated cDNAs in human or mouse cells (1). Although these approaches have yielded remarkable results, they are typically hampered by at least two caveats. First, the expression is achieved by transient or stable transfection of cDNAs, often resulting in over-expression of the target allele at levels that do not recapitulate what occurs in human cancers. Second, the expression of the mutated cDNA is achieved under the control of nonendogenous viral promoters. As a result, the mutated alleles cannot be appropriately (endogenously) modulated in the target cells. While such systems in which mutated oncogenes are ectopically expressed under exogenous promoters have been instrumental in dissecting their oncogenic properties, they have also led to controversial results. For example, studies focused on oncogene-mediated transformation and senescence have generated conflicting data depending on whether the cancer alleles were ectopically expressed or permanently introduced in the genome of mouse or human cells (2-5). To address the limitation of current models, we have used targeted homologous recombination to introduce (knock-in, KI) a panel of cancer alleles in human somatic cells. Specifically, we focused on EGFR, KRAS, BRAF, and PIK3CA mutated alleles that are found in multiple cancer types. Mutant cells have then been used to study the biochemical and transforming potential of common cancer alleles and to identify genotype-specific ...

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Section: Knock-in Cells Display Drug Responses Resembling Those Of Tumentioning

confidence: 99%

Replacement of normal with mutant alleles in the genome of normal human cells unveils mutation-specific drug responses

Nicolantonio

Arena

Gallicchio

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

124

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“…In mammalian cells, the p110α and p110β isoforms are expressed ubiquitously, whereas p110γ expression is restricted to immune cells (1,3,4). Aberrant PI3K signaling is frequently found in human cancers, either as a consequence of receptor tyrosine kinase mutation or amplification, loss, or inactivation of the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor, or by gain-of-function or amplification of PI3K genes (5)(6)(7)(8)(9). The oncogenic hotspot mutations of PIK3CA are found within the p110α helical domain (E545K and E542K) or the kinase domain (H1047R).…”

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confidence: 99%

ΔNp63α is a common inhibitory target in oncogenic PI3K/Ras/Her2-induced cell motility and tumor metastasis

Liang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Activation of phosphatidylinositol 3 kinase (PI3K), Ras, and Her2 signaling plays a critical role in cancer development. Hotspot constitutive activating mutations in oncogenes, such as PIK3CA encoding the p110α catalytic subunit or RAS, as well as overexpression of Her2, are frequently found in human tumors and cancers. It has been well established that activation of these oncogenes profoundly promotes tumor metastasis, whereas decreased expression of ΔNp63α, the major protein isoform of the p53-related p63 expressed in epithelial cells, has been associated with cancer metastasis. In this study, we demonstrate that hotspot oncogenic mutations on PIK3CA and RAS, including p110α H1047R , K-Ras G12V , and H-Ras G12V , as well as activation of Her2, all led to suppression of ΔNp63α expression via Akt-fork-head transcription factor 3a (Akt-FOXO3a) signaling, resulting in increased cell motility and tumor metastasis. Expression of ΔNp63α effectively reversed p110α H1047R -, K-Ras G12V -, H-Ras G12V -, or Her2-induced cell motility in vitro and tumor metastasis in mouse models. We show that ΔNp63α was a direct FOXO3a transcriptional target and that expression of FOXO3a and ΔNp63α was correlated in human cancer biopsy samples. Together, these results demonstrate that ΔNp63α is a common inhibitory target of oncogenic PI3K, Ras, and Her2, and that ΔNp63α may function as a critical integrator of oncogenic signaling in cancer metastasis.PIK3CA | Ras | Her2 | ΔNp63α | cancer metastasis

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“…NSCLCs in smokers and nonsmokers have different molecular signatures; NSCLC cells in smokers harbor mutations mainly in Ras and p53 genes while epidermal growth factor receptor (EGFR) mutations are less prevalent (60,64). On the other hand, NSCLC cells in nonsmokers show more widespread mutations in the kinase domain of EGFR encoded by exons 18 to 24 (38) and show high expression of p27 and Akt1 (59,69). Interestingly, the EGFR gene is amplified or overexpressed in latestage cancers in both smokers and nonsmokers, indicating that EGFR activity contributes to the growth and progression of NSCLC (54,58,60).…”

mentioning

confidence: 99%

ID1 Facilitates the Growth and Metastasis of Non-Small Cell Lung Cancer in Response to Nicotinic Acetylcholine Receptor and Epidermal Growth Factor Receptor Signaling

Pillai

Rizwani

et al. 2011

Molecular and Cellular Biology

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PIK3CA Mutations and Copy Number Gains in Human Lung Cancers

Cited by 384 publications

References 38 publications

Replacement of normal with mutant alleles in the genome of normal human cells unveils mutation-specific drug responses

Replacement of normal with mutant alleles in the genome of normal human cells unveils mutation-specific drug responses

ΔNp63α is a common inhibitory target in oncogenic PI3K/Ras/Her2-induced cell motility and tumor metastasis

ID1 Facilitates the Growth and Metastasis of Non-Small Cell Lung Cancer in Response to Nicotinic Acetylcholine Receptor and Epidermal Growth Factor Receptor Signaling

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