Expression and mutation status of candidate kinases in multiple myeloma

Claudio, Jaime O.; Zhan, Fenghuang; Zhuang, Lin; Khaja, Razi; Zhu, Yunping; Sivananthan, Kamalanayani; Trudel, Suzanne; Masih‐Khan, Esther; Fonseca, Rafaël; Bergsagel, P. Leif; Scherer, Stephen W.; Shaughnessy, John D.; Stewart, A. Keith

doi:10.1038/sj.leu.2404612

Cited by 13 publications

(11 citation statements)

References 5 publications

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“…These and the D54 glioblastoma line were sequenced for PIK3CA mutations using published primer sequences (Table S1) [6]. While 081110 was devoid of mutations in this subunit, 081024 carried 3 mutations on exon 13, each of which has been documented as a SNP (NCBI dbSNP database) [43]. These mutations represented the following amino acid substitutions: V680L, E707K, and L719V.…”

Section: Resultsmentioning

confidence: 99%

Abrogation of PIK3CA or PIK3R1 reduces proliferation, migration, and invasion in glioblastoma multiforme cells

et al. 2011

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Glioblastoma multiforme (GBM) is a highly invasive and deadly brain tumor. Tumor cell invasion makes complete surgical resection impossible and reduces the efficacy of other therapies. Genome-wide analyses of mutations, copy-number changes, and expression patterns have provided new insights into genetic abnormalities common in GBM. We analyzed published data and identified the invasion and motility pathways most frequently altered in GBM. These were most notably the focal adhesion and integrin signaling, and extracellular matrix interactions pathways. We mapped alterations in each of these pathways and found that they included the catalytic PIK3CA and regulatory PIK3R1 subunit genes of the class IA PI3K. Knockdown of either of these genes separately in GBM cell lines by lentiviral-mediated shRNA expression resulted in decreased proliferation, migration, and invasion in all lines tested. FAK activity was reduced by knockdown of either PIK3CA or PIK3R1, and MMP2 levels were reduced by knockdown of PIK3R1. We conclude that PIK3R1, like PIK3CA, is a potential therapeutic target in GBM and that it also influences tumor cell growth and motility.

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Section: Resultsmentioning

confidence: 99%

Abrogation of PIK3CA or PIK3R1 reduces proliferation, migration, and invasion in glioblastoma multiforme cells

et al. 2011

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“…Accordingly, Sprouty protein expression is frequently deregulated in different tumor entities and this may contribute to malignancy. In NSCLC, Sprouty2 expression is downregulated at both the mRNA and the protein level in the malignant tissue of the lung cancer patients and its re-expression interferes with cell proliferation [190][191][192][193] [194] [195] [ [196][197][198] Transmembrane Bladder Prostate [190,191,193,199] [194] Cytoplasmic Brain, Testis, Head and neck, Bladder [200][201][202][203][204] FGFR4 Extracellular Rhabdomyosarcoma Lung…”

Section: Deregulation Of Signal Attenuationmentioning

confidence: 99%

Targeting fibroblast-growth-factor-receptor-dependent signaling for cancer therapy

Heinzle

Sutterlüty

Grusch

et al. 2011

Expert Opinion on Therapeutic Targets

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Strategies for targeting FGFR-signaling for cancer therapy are very promising, but need to be carefully developed based on the physiological roles of FGF signaling. Preventive measures may be necessary for protection from FGF-related side effects. Combined targeting of several receptor tyrosine kinases or combination with other therapies may be a useful way of avoiding or ameliorating side effects. FGF-related markers of prognosis and therapy response still need to be investigated.

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“…Despite advances in systemic and supportive therapies, MM remains a fatal disease. Mutations in receptor tyrosine kinase (TK) and RAS oncogene gene families resulting in constitutive activation of the gene product have been reported in myeloma [2-6]. However, a recent mutational screening of 31, receptor TK gene domains revealed few disruptive mutations in MM [2].…”

Section: Introductionmentioning

confidence: 99%

“…Mutations in receptor tyrosine kinase (TK) and RAS oncogene gene families resulting in constitutive activation of the gene product have been reported in myeloma [2-6]. However, a recent mutational screening of 31, receptor TK gene domains revealed few disruptive mutations in MM [2]. Furthermore, mutational studies in RAS pathway genes, have described conflicting results in terms of their existence and frequency in MM [3, 5-9].…”

Section: Introductionmentioning

confidence: 99%

Resequencing analysis of the candidate tyrosine kinase and RAS pathway gene families in multiple myeloma

et al. 2012

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Multiple myeloma (MM) is an incurable, B-cell malignancy, characterized by the clonal proliferation and accumulation of malignant plasma cells in bone marrow. Despite recent advances in understanding of genomic aberrations, a comprehensive catalogue of clinically actionable mutations in MM is just beginning to emerge. The tyrosine kinase (TK) and RAS oncogenes, which encode important regulators of various signaling pathways, are among the most frequently altered gene families in cancer. To clarify the role of TK and RAS genes in pathogenesis of MM, we performed a systematic, targeted screening of mutations on prioritized RAS and TK genes, in CD138 sorted bone marrow specimens from 42 untreated patients. We identified a total of 24 mutations in KRAS, PIK3CA, INSR, LTK and MERTK genes. In particular, seven novel mutations in addition to known KRAS mutations were observed. Prediction analysis tools, PolyPhen and SIFT were used to assess the functional significance of these novel mutations. Our analysis predicted that these mutations may have a deleterious effect, resulting in functional alteration of proteins involved in the pathogenesis of myeloma. While further investigation is needed to determine the functional consequences of these proteins, mutational testing of the RAS and TK genes in larger myeloma cohorts might be also useful to establish the recurrent nature of these mutations.

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Expression and mutation status of candidate kinases in multiple myeloma

Cited by 13 publications

References 5 publications

Abrogation of PIK3CA or PIK3R1 reduces proliferation, migration, and invasion in glioblastoma multiforme cells

Abrogation of PIK3CA or PIK3R1 reduces proliferation, migration, and invasion in glioblastoma multiforme cells

Targeting fibroblast-growth-factor-receptor-dependent signaling for cancer therapy

Resequencing analysis of the candidate tyrosine kinase and RAS pathway gene families in multiple myeloma

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