PI3K signaling pathway is activated by PIK3CA mRNA overexpression and copy gain in prostate tumors, but PIK3CA, BRAF, KRAS and AKT1 mutations are infrequent events

Agell, Laia; Hernández, Sílvia; Salido, Marta; Muga, Silvia de; Juanpere, Núria; Arumí-Uría, Montserrat; Menéndez, Sílvia; Lorenzo, Marta; Lorente, José A.; Serrano, Sergio; Lloreta, Josep

doi:10.1038/modpathol.2010.208

Cited by 40 publications

(31 citation statements)

References 36 publications

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“…PIK3CA gene amplification and mutations can be detected in advanced prostate tumors (Agell et al, 2011; Robinson et al, 2015; Sarker et al, 2009; Sun et al, 2009). However, the most common alteration in this pathway is the loss of PTEN, a phosphatase for the PI3K product PIP3.…”

Section: Introductionmentioning

confidence: 99%

Protein Kinase C Epsilon Cooperates with PTEN Loss for Prostate Tumorigenesis through the CXCL13-CXCR5 Pathway

et al. 2017

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Summary PKCε, an oncogenic member of the PKC family, is aberrantly overexpressed in epithelial cancers. To date, little is known about functional interactions of PKCε with other genetic alterations as well as the effectors contributing to its tumorigenic and metastatic phenotype. Here, we demonstrate that PKCε cooperates with the loss of tumor suppressor Pten for the development of prostate cancer in a mouse model. Mechanistic analysis revealed that PKCε overexpression and Pten loss individually and synergistically up-regulate the production of the chemokine CXCL13, which involves the transcriptional activation of the CXCL13 gene via the non-canonical NF-κB pathway. Notably, targeted disruption of CXCL13 or its receptor CXCR5 in prostate cancer cells impaired their migratory and tumorigenic properties. In addition to providing evidence for an autonomous vicious cycle driven by PKCε, our studies identified a compelling rationale for targeting the CXCL13:CXCR5 axis for prostate cancer treatment.

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Section: Introductionmentioning

confidence: 99%

Protein Kinase C Epsilon Cooperates with PTEN Loss for Prostate Tumorigenesis through the CXCL13-CXCR5 Pathway

et al. 2017

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“…Activating mutations to PIK3CA , the gene encoding the p110α catalytic subunit of PI3K, are found in several tumor types, including glioblastoma (27%), breast (18%), colorectal (16% of non-hypermutated tumors), cervical (33%), head and neck squamous cell cancer (HNSCC; 6–8%), and non-small cell lung cancer (NSCLC; 2–6%) [2,4–9]. Increased PIK3CA copy numbers are seen in prostate cancer (28%), squamous histology NSCLC (33%), and HNSCC (45%) [10–12]. The phosphatase and tensin homolog ( PTEN ) tumor suppressor gene, which inhibits PI3K signaling, may be lost via deletion (25% of melanoma, breast, and prostate cancers), mutation, or epigenetic suppression [13–16].…”

Section: Introductionmentioning

confidence: 99%

A randomized, phase 2 trial of docetaxel with or without PX-866, an irreversible oral phosphatidylinositol 3-kinase inhibitor, in patients with relapsed or metastatic head and neck squamous cell cancer

et al. 2015

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SUMMARY Introduction The phosphotidylinositol-3 kinase (PI3K)/serine–threonine kinase (AKT)/mammalian target of rapamycin (mTOR) signaling pathway is frequently altered in head and neck squamous cell cancer (HNSCC). PX-866 is an oral, irreversible, pan-isoform inhibitor of PI3K. Preclinical models revealed synergy with docetaxel and a phase 1 trial demonstrated tolerability of this combination. This randomized phase 2 study evaluated PX-866 combined with docetaxel in patients with advanced, refractory HNSCC. Methods Patients with locally advanced, recurrent or metastatic HNSCC who had received at least one and no more than two prior systemic treatment regimens were randomized (1:1) to a combination of docetaxel (75 mg/m2 IV every 21 days) with or without PX-866 (8 mg PO daily; Arms A and B, respectively). The primary endpoint was progression free survival (PFS). Secondary endpoints included objective response rate (RR), overall survival (OS), toxicity, and correlation of biomarker analyses with efficacy outcomes. Results 85 patients were enrolled. There was a non-significant improvement in response rate in the combination arm (14% vs. 5%; P = 0.13). Median PFS was 92 days in Arm A and 82 days in Arm B (P = 0.42). There was no difference in OS between the two arms (263 vs. 195 days; P = 0.62). Grade 3 or higher adverse events were infrequent, but more common in the combination arm with respect to diarrhea (17% vs. 2%), nausea (7% vs. 0%), and febrile neutropenia (21% vs. 5%); grade 3 or higher anemia was more frequent in arm B (7% vs. 27%). PIK3CA mutations or PTEN loss were infrequently observed. Conclusion The addition of PX-866 to docetaxel did not improve PFS, RR, or OS in patients with advanced, refractory HNSCC without molecular pre-selection.

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“…Activating mutations to PIK3CA , the gene encoding the p110 α catalytic subunit of PI3K, are found in several tumour types, including glioblastoma (27%), breast (18%), colorectal (16% of non-hypermutated tumours), cervical (33%), endometrial (39%), squamous cell carcinoma of the head and neck (SCCHN; 6–8%), and non-small cell lung cancer (NSCLC; 2–6%) (Levine et al , 2005; Hayes et al , 2006; Samuels and Ericson, 2006; Miyake et al , 2008; Agrawal et al , 2011; Stransky et al , 2011; Cancer Genome Atlas Network, 2012). Increased PIK3CA copy numbers are seen in prostate cancer (28%), squamous histology NSCLC (33%), and SCCHN (45%) (Yamamoto et al , 2008; Agell et al , 2011; Morris et al , 2011). The phosphatase and tensin homolog ( PTEN ) tumour suppressor gene, which inhibits PI3K signalling, may be lost via deletion (25% of melanoma, breast, and prostate cancers), mutation, or epigenetic suppression (Pesche et al , 1998; Tokunaga et al , 2007; Cancer Genome Atlas Research Network, 2008; Carracedo and Pandolfi, 2008).…”

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A multicenter phase 1 study of PX-866 in combination with docetaxel in patients with advanced solid tumours

Bowles

Senzer

et al. 2013

Br J Cancer

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Background:This phase I, dose-finding study determined the safety, maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), pharmacokinetics, and antitumour activity of PX-866, a phosphatidylinositol 3-kinase inhibitor, combined with docetaxel in patients with incurable solid tumours.Methods:PX-866 was administered at escalating doses (4–8 mg daily) with docetaxel 75 mg m−2 intravenously every 21 days. Archived tumour tissue was assessed for potential predictive biomarkers.Results:Forty-three patients were enrolled. Most adverse events (AEs) were grade 1 or 2. The most frequent study drug-related AE was diarrhoea (76.7%), with gastrointestinal disorders occurring in 79.1% (docetaxel-related) and 83.7% (PX-866-related). No dose-limiting toxicities were observed. The RP2D was 8 mg, the same as the single-agent MTD. Co-administration of PX-866 and docetaxel did not affect either drug's PKs. Best responses in 35 evaluable patients were: 2 partial responses (6%), 22 stable disease (63%), and 11 disease progression (31%). Eleven patients remained on study for >180 days, including 8 who maintained disease control on single-agent PX-866. Overall median progression-free survival (PFS) was 73.5 days (range: 1–569). A non-significant association between longer PFS for PIK3CA-MUT/KRAS-WT vs PIK3CA-WT/KRAS-WT was observed.Conclusion:Treatment with PX-866 and docetaxel was well tolerated, without evidence of overlapping/cumulative toxicity. Further investigation with this combination is justified.

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PI3K signaling pathway is activated by PIK3CA mRNA overexpression and copy gain in prostate tumors, but PIK3CA, BRAF, KRAS and AKT1 mutations are infrequent events

Cited by 40 publications

References 36 publications

Protein Kinase C Epsilon Cooperates with PTEN Loss for Prostate Tumorigenesis through the CXCL13-CXCR5 Pathway

Protein Kinase C Epsilon Cooperates with PTEN Loss for Prostate Tumorigenesis through the CXCL13-CXCR5 Pathway

A randomized, phase 2 trial of docetaxel with or without PX-866, an irreversible oral phosphatidylinositol 3-kinase inhibitor, in patients with relapsed or metastatic head and neck squamous cell cancer

A multicenter phase 1 study of PX-866 in combination with docetaxel in patients with advanced solid tumours

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