Reduction of PTEN protein and loss of epidermal growth factor receptor gene mutation in lung cancer with natural resistance to gefitinib (IRESSA)

Abstract

Gefitinib (IRESSA), an epidermal growth factor receptor (EGFR) tyrosine kinase (TK) inhibitor, has antitumour activity in the advanced non-small-cell lung cancer (NSCLC) setting. However, in chemotherapy-naïve patients with advanced NSCLC, the addition of gefitinib to standard chemotherapy regimens failed to increase survival. These results suggest the need for improved patient selection and combination rationales for targeted therapies. We have identified subpopulations of an adenocarcinoma cell line that are naturally resistant to gefitinib, and have analysed the cDNA expression profiles, genomic status of EGFR gene and the effect of gefitinib on signalling pathways in these cell lines in order to identify key mechanisms for naturally acquired resistance to gefitinib. Gefitinib-resistant subpopulations demonstrated increased Akt phosphorylation (not inhibited by gefitinib), reduced PTEN protein expression and loss of the EGFR gene mutation when compared with parental cell lines. These differences in Akt and PTEN protein expression were not evident from the cDNA array profiles. These data suggests that (1) the EGFR gene mutation may be possibly lost in some cancer cells with other additional mechanisms for activating Akt, (2) reintroduction of PTEN or pharmacological downregulation of the constitutive PI3K -Akt-pathway activity may be an attractive therapeutic strategy in cancers with gefitinib resistance.

Long-term exposure of leukemia cells to multi-targeted tyrosine kinase inhibitor induces activations of AKT, ERK and STAT5 signaling via epigenetic silencing of the PTEN gene

“…42 In addition, homozygous deletion of the PTEN gene was associated with the development of gefitinib resistance in lung cancer cells. 43 Interestingly, other investigators showed that irradiation restored PTEN expression in H-157 lung cancer cells with a low expression of PTEN and sensitized these cells to gefitinib in vitro. 44 Furthermore, forced expression of PTEN in prostate cancer cells by a doxycycline-inducible system sensitized these cells to gefitinib.…”

The role of PTEN signaling perturbations in cancer and in targeted therapy

“…In a similar manner, the general activation of the PI3K pathway (by PTEN loss or PI3K mutation) in colon cancer cell lines predicts lack of response to cetuximab (Frattini et al, 2007;Jhawer et al, 2008). A reduction in PTEN expression is also associated with gefitinib resistance (Kokubo et al, 2005). Interestingly K-Ras mutations, which are known to activate PI3K, are also associated with poor outcome after certuximab treatment (Lievre et al, 2006).…”

“…Specifically, activating mutations and gene amplifications of EGFR and HER2 are found in ovarian, breast and other cancers (Kokubo et al, 2005;Moasser, 2007;Vermeij et al, 2008). Particular combinations of growth factor receptor complexes (such as HER2/HER3 and EGFR/GAB1) are able to activate PI3K in a context-dependent manner (Wallasch et al, 1995;Laffargue et al, 1999).…”

“…Recently, the activation of PI3K pathway has been shown to significantly correlate with the lack of efficacy of several targeted therapies including trastuzumab, which targets HER2/ErbB2, as well as with getfitinib and cetuximab, both of which target EGFR (Nagata et al, 2004;Kokubo et al, 2005;Berns et al, 2007;Frattini et al, 2007;Jhawer et al, 2008). Using stringent criteria for the definition of PTEN loss, Nagata et al (2004) found that there was a significantly worse response to trastuzumab (in combination with taxane) in PTEN negative tumors.…”

Frequent mono-allelic loss associated with deficient PTEN expression in imatinib-resistant gastrointestinal stromal tumors

“…3 Similarly, it promotes resistance to EGFR tyrosine kinase inhibitors in glioblastoma, colon, and lung cancer. [4][5][6] In gastrointestinal stromal tumors (GISTs), KIT and PDGFRA are fundamental therapeutic targets; however, the majority of GIST patients eventually develop resistance to imatinib mesylate and to other receptor tyrosine kinase inhibitors currently applied in the clinic. 7 This resistance is mainly due to the re-activation of KIT signaling by the acquisition of secondary KIT mutations.…”