Lack of AKT activation in lung cancer cells with EGFR mutation is a novel marker of cetuximab sensitivity

Abstract

Epidermal growth factor receptor (EGFR) mutation is the best marker of sensitivity to the EGFR tyrosine kinase inhibitor gefitinib, but a marker for the anti-EGFR antibody cetuximab has not been identified in lung cancer. The present study investigated markers for sensitivity to cetuximab. Sensitivity to cetuximab and gefitinib was compared with EGFR expression, EGFR and KRAS mutation, and EGFR gene copy numbers in lung cancer cell lines. We also studied the effect of these agents on the activation of EGFR, ERK, AKT, and STAT3 in cetuximab-sensitive and -resistant cell lines. We found one cetuximab-sensitive cell line with EGFR mutation among 19 lung cancer cell lines. Analysis of molecules downstream from EGFR revealed that AKT phosphorylation was suppressed in this cell line. Augmentation of AKT phosphorylation by transfection of a plasmid induced resistance to cetuximab. Acquisition of cetuximab resistance was associated with AKT activation in this cell line, while pharmacological inhibition of AKT markedly enhanced the growth inhibitory effect of cetuximab. Dephosphorylation of AKT in association with EGFR mutation is a candidate marker for sensitivity to cetuximab, and combined use of an AKT pathway inhibitor with cetuximab could be a novel therapeutic strategy for lung cancer.

Three-Dimensional Lung Tumor Microenvironment Modulates Therapeutic Compound Responsiveness In Vitro – Implication for Drug Development

“…Cetuximab, on the other hand, did not alter cell proliferation in either cell culture microenvironment. This confirms previous reports that many different lung tumor cell lines are resistant to Cetuximab, showing no inhibition in cell proliferation [56]. Another study demonstrated that monolayer proliferation of H292 (wildtype EGFR) was not inhibited by Cetuximab when HGF was added [44].…”

Akt Activation Mediates Acquired Resistance to Fibroblast Growth Factor Receptor Inhibitor BGJ398

“…While epithelial-mesenchymal transition was primarily implicated as mediating resistance to the FGFR inhibitors, increased levels of pAkt (along with pSTAT and pERK) were observed in the resistant cell lines and treatment with pictilisib, a PI3K inhibitor, was able to restore sensitivity (44). Further, acquired resistance to cetuximab, a monoclonal antibody for EGFR, was associated with Akt activation in lung cancer cell lines and pharmacological inhibition of Akt with the PI3K inhibitor LY294002 enhanced the inhibitory effect of cetuximab (45). Thus, there is interest in whether Akt or PI3K inhibitors could overcome resistance in cancers driven by receptor tyrosine kinases.…”

Resveratrol Sensitizes Colorectal Cancer Cells to Cetuximab by Connexin 43 Upregulation-Induced Akt Inhibition

“…For example, phosphoinositide 3-kinase catalytic subunit α has activating mutations in some metastatic colorectal cancer tissues, which are used to predict cetuximab resistance (32). The status of Akt activation also relates to anti-EGFR therapy resistance in head and neck squamous cell carcinoma (33) and lung cancer (2). Hence, the PI3K-Akt pathway cannot be totally inhibited by cetuximab.…”

“…However, there are other mechanisms to activate Akt besides the phosphorylation of EGFR, and resistance emerges if Akt maintains activation during cetuximab therapy. Some research has found that cetuximab resistance relates to Akt activation in many cell lines, phosphorylated Akt (p-Akt) still occurs at a certain level after cetuximab treatment in these cells, and inhibiting the Akt pathway with other reagents is an effective strategy to sensitize these cell lines to cetuximab (2). Resveratrol (3,5,4 ′ -trihydroxy-trans-stilbene) is a polyphenolic compound that has been shown to have various anticancer, anti-inflammatory, and antioxidant activities (3,4).…”