PTEN expression controls cellular response to cetuximab by mediating PI3K/AKT and RAS/RAF/MAPK downstream signaling in KRAS wild-type, hormone refractory prostate cancer cells

Abstract

Abstract. Overexpression of epidermal growth factor receptor (EGFR) and mutation of pten tumor suppressor gene in human cancer cells leads to activated EGFR downstream signaling including PI3-kinase/AKT (PI3K/AKT) and/or mitogen-activated protein kinases (RAS/RAF/MAPK) and have been linked to resistance to anti-EGFR targeted therapies. Cetuximab is a chimeric IgG1 monoclonal antibody that binds the EGFR with high specificity and have been developed as promising therapeutic anticancer treatments in several solid tumors, including colorectal and head and neck squamous cell carcinomas. Cetuximab activity is related to PI3K/AKT and RAS/RAF/MAPK signaling pathways functionality and its activity has been shown to be higher in wild-type KRAS tumors. To study the influence of PTEN expression on cell response to cetuximab, we used wild-type KRAS, PTEN-null, EGFR overexpressing PC3 prostate cancer cells. Reintroduction of PTEN significantly reduced the constitutive overexpression of phosphorylated-AKT (p-AKT) and downstream kinases (p-GSK3ß and p-P70S6 kinase) as well as phosphorylated-ERK1/2 (p-ERK1/2) and consequently significantly restored cetuximab-induced cell growth inhibition and apoptosis induction. Taken together, the results achieved in the present study show that PTEN controls the cellular response to cetuximab in KRAS wild-type prostate carcinoma PC3 cells through the regulation of AKT phosphorylation and restoration of the functionality of EGFR downstream signaling. Extrapolation of these findings to clinical situation, suggests that the assessment of EGFR downstream signaling functionality could be proposed as a diagnostic response predictive marker for anti-EGFR targeted therapies.

PTENInhibits Cell Proliferation, Promotes Cell Apoptosis, and Induces Cell Cycle Arrest via Downregulating the PI3K/AKT/hTERTPathway in Lung Adenocarcinoma A549 Cells

“…Inactivation of PTEN is a key event in tumorigenesis and tumor development, and in fact it has the highest frequency of mutation in cancer after the P53 gene [6]. Currently, the tumor suppressing mechanism of the PTEN gene likely involves several candidate pathways, including the FAK pathway [7], the MAPK pathway [8, 9], and the PI3K/AKT pathway [10, 11]. Currently, the PI3K/AKT pathway is regarded as the key pathway by which PTEN exerts its antioncogenic effects.…”

Optimal Cetuximab Contact Concentration Using a Collagen Gel Droplet- Embedded Culture Drug Chemosensitivity Test in Human Oral Squamous Carcinoma Cell Lines

“…However, EGFRvIII is a mutant form of EGFR that is expressed in 40% of head and neck cancers [34] and is believed to be involved in cetuximab resistance [35]. The tumor suppressor gene PTEN blocks the PI3K/AKT signal transmission pathway, and previous studies have suggested that the absence or diminished expression of PTEN contributes to cetuximab resistance [36,37].…”

Targeting PI3K/Akt signaling in prostate cancer therapy

“…It has been reported that overexpression of PTEN in prostate cancer inhibits PI3K/Akt signaling. Then, a significant decrease occurs in expression levels of GSK‐3β, P70S6 kinase and ERK1/2 as downstream targets, leading to apoptotic cell death in prostate tumor and improving response to cetuximab (Bouali et al 2009). As it was mentioned, ADT is employed for prostate cancer suppression, but there are reports of resistance.…”