Analysis of the PI3K-AKT-mTOR pathway in penile cancer: evaluation of a therapeutically targetable pathway

Abstract

ObjectivesTo determine whether phosphatidylinositol-4,5-bisphosphate 3- kinase, catalytic subunit alpha (PIK3CA) copy number gain is common and could prove a useful marker for the activation status of the PI3K-AKT-mTOR pathway in penile squamous cell carcinoma (PSCC).MethodsFresh frozen tissue and archival blocks were collected from 24 PSCC patients with 15 matched normal penile epithelium (NPE) tissue from St George’s Hospital. PIK3CA mutational and copy number status (CNS) was assessed via Sanger sequencing and fluorescence in-situ hybridisation, respectively. PIK3CA RNA expression was quantified using TaqMan gene expression assay. HPV DNA was detected with INNO-LiPA assay. p-AKT and p-mTOR protein expression were assessed using western blot and immunohistochemistry.ResultsPIK3CA copy number gain was found in 11/23 (48%) patients, with mutations present in only 2/24 (8%) patients. In comparison to NPE, PSCC showed significantly lower PIK3CA RNA expression (p=0.0007), p-AKT (Ser473) nuclear immunoexpression (p=0.026) and protein expression of p-AKT (Thr308) (p=0.0247) and p-mTOR (Ser2448) (p=0.0041). No association was found between PIK3CA CNS and p-AKT and p-mTOR protein expression.ConclusionBased on our results the PI3K-AKT-mTOR pathway is not a key driver in PSCC carcinogenesis and the therapeutic targeting of this pathway is unlikely to produce significant clinical benefit.

MicroRNA Involvement in Signaling Pathways During Viral Infection

“…Prior studies have demonstrated the fact that the overexpression of miR-199a-5p plays an important role in enhancing the pro-survival PI3K/Akt pathway. Their results have shown that by decreasing the miR-199a-5p levels, the phosphorylated Akt (p-Akt) levels are also significantly diminished, therefore leading to the proposed mechanism through which miR-199a-5p exerts its actions by promoting Akt phosphorylation (g; Diehl and Schaal, 2013;Wang et al, 2015;Adimonye et al, 2018).…”

Genomic profiling reveals the pivotal role of hrHPV driving copy number and gene expression alterations, including mRNA downregulation of TP53 and RB1 in penile cancer

“…A few numbers of studies have performed PeCa genomic profiling by array comparative genomic hybridization (aCGH), describing copy number alterations (CNAs), and their potential prognostic values in association with HPV infection 6,7 . Comprehensive genomic profiling (CGP) has also been performed suggesting the involvement of potential driver genes, such as the PIK3CA oncogene (affected mostly by point mutations) and EGFR (amplified) 8 . Additionally, other tyrosine kinase receptor family ERBB members ( EGFR , ERBB3 , and ERBB4 ), which regulate the cell cycle by activating the PI3K/AKT pathway downstream genes, were associated with PeCa by immunohistochemistry (IHC) analysis, 9 and most recently, it was suggested that specific genes of the mTOR, DNA repair, and tyrosine kinase pathways could be used as potential druggable targets for metastatic penile squamous cell carcinomas 10 …”

“…6,7 Comprehensive genomic profiling (CGP) has also been performed suggesting the involvement of potential driver genes, such as the PIK3CA oncogene (affected mostly by point mutations) and EGFR (amplified). 8 Additionally, other tyrosine kinase receptor family ERBB members (EGFR, ERBB3, and ERBB4), which regulate the cell cycle by activating the PI3K/AKT pathway downstream genes, were associated with PeCa by immunohistochemistry (IHC) analysis, 9 and most recently, it was suggested that specific genes of the mTOR, DNA repair, and tyrosine kinase pathways could be used as potential druggable targets for metastatic penile squamous cell carcinomas. 10 It has been also shown that the HPV oncoproteins E6 and E7 can lead to the degradation of proteins with tumor suppressor function, such as p53 and pRB, and also promote the activation of proto-oncogenes, such as C-MYC, mediated by HPV insertion on fragile sites into the host genome.…”

The Biomarker Potential of Caveolin-1 in Penile Cancer

“…However, when used as second-line treatment for patients with refractory disease only modest results were achieved ( 81 ). Similar the EGFR-dependent activation of the Ras/Raf/mitogen-activated protein kinase-extracellular signal-regulated kinase-signaling pathway, and as shown for multiple other cancers, activation of the phosphatidylinositol-3-kinase (PI3K), protein kinase B (PKB/AKT), and mammalian target of rapamycin (mTOR) pathway is a frequent event in carcinogenesis that facilitates tumor formation, progression and therapy resistance ( 82 – 84 ). Herein, a high frequency of PIK3CA (the catalytic subunit alpha of PI3K) copy number gains were reported as primary method for the activation of the PI3K-AKT-mTOR pathway in penile carcinogenesis ( 82 , 83 , 85 ).…”