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

Abstract

The phosphatidylinositol 3-kinase (PI3K)-AKT and RAS-MAPK pathways are deregulated in a wide range of human cancers by gain or loss of function in several of their components. Our purpose has been to identify genetic alterations in members of these pathways in prostate cancer. A total of 102 prostate tumors, 79 from prostate cancer alone (group G1) and 23 from bladder and prostate cancer patients (G2), are the subject of this study. In 20 of these 23, the bladder tumors were also analyzed. PIK3CA, KRAS, BRAF and AKT1 mutations were analyzed by direct sequencing, and BRAF also by pyrosequencing. PIK3CA quantitative mRNA expression and fluorescence in situ hybridization (FISH) gains were tested in 25 and 32 prostate tumors from both groups (G1 and G2), respectively. Immunohistochemistry for pAKT was performed in 55 prostate tumors. Of 25 prostate tumors, 10 (40%) had PIK3CA mRNA overexpression that was statistically associated with Gleason score Z7 (P ¼ 0.018). PIK3CA copy gain was detected in 9 of 32 (28%) prostate tumors. Of 20 bladder tumors, 3 (15%) displayed mutations in PIK3CA, KRAS and AKT1, the corresponding prostate tumors being wt. We also detected a previously not reported PIK3CA polymorphism (IVS9 þ 91) in two prostate tumors. In all, 56% of prostate tumors overexpressed pAKT. There is a statistical association (Po0.0001) of strong pAKT immunostaining with high Gleason score, and with PIK3CA alterations (mRNA overexpression and/or FISH gains). PIK3CA gene is deregulated by mRNA overexpression and DNA gain in B40 and 28% of prostate tumors, respectively. High-grade prostate tumors are associated with PIK3CA mRNA overexpression, but not with FISH status. PIK3CA, BRAF, KRAS and AKT1 mutations are very infrequent events in prostate tumors. However, PI3K signaling pathway is activated by PIK3CA FISH gain and/or mRNA overexpression, leading to an increased pAKT protein expression.

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

“…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.…”

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

“…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].…”

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

“…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).…”