Journal Article

Tyr1068-phosphorylated epidermal growth factor receptor (EGFR) predicts cancer stem cell targeting by erlotinib in preclinical models of wild-type EGFR lung cancer

Mottolese, M, Policicchio, E, Eramo, A, Pilozzi, E, Milella, M, Visca, P, Salvati, V, Tartaglia, M, Fecchi, K, Sette, G, Gallo, E, Duranti, E, De Maria, R

2015

Overview

Tyrosine kinase inhibitors (TKIs) have shown strong activity against non-small-cell lung cancer (NSCLC) patients harboring activating epidermal growth factor receptor (EGFR) mutations. However, a fraction of EGFR wild-type (WT) patients may have an improvement in terms of response rate and progression-free survival when treated with erlotinib, suggesting that factors other than EGFR mutation may lead to TKI sensitivity. However, at present, no sufficiently robust clinical or biological parameters have been defined to identify WT-EGFR patients with greater chances of response. Therapeutics validation has necessarily to focus on lung cancer stem cells (LCSCs) as they are more difficult to eradicate and represent the tumor-maintaining cell population. Here, we investigated erlotinib response of lung CSCs with WT-EGFR and identified EGFR phosphorylation at tyrosine1068 (EGFR tyr1068 ) as a powerful biomarker associated with erlotinib sensitivity both in vitro and in preclinical CSC-generated xenografts. In contrast to the preferential cytotoxicity of chemotherapy against the more differentiated cells, in EGFR tyr1068 cells, erlotinib was even more active against the LCSCs compared with their differentiated counterpart, acquiring potential value as CSC-directed therapeutics in the context of WT-EGFR lung cancer. Although tumor growth was inhibited to a similar extent during erlotinib or chemotherapy administration to responsive tumors, erlotinib proved superior to chemotherapy in terms of higher tolerability and reduced tumor aggressiveness after treatment suspension, substantiating the possibility of preferential LCSC targeting, both in adenocarcinoma (ADC) and squamous cell carcinoma (SCC) tumors. We conclude that EGFR tyr1068 may represent a potential candidate biomarker predicting erlotinib response at CSC-level in EGFR-WT lung cancer patients. Finally, besides its invariable association with erlotinib sensitivity in EGFR-WT lung CSCs, EGFR tyr1068 was associated with EGFR-sensitizing mutations in cell lines and patient tumors, with relevant diagnostic, clinical and therapeutic implications.

• Publisher: Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group
• Subject: 13/31 / 631/67/1059/99 / 631/67/1612 / 631/67/71 / 631/80/458/1733 / 64 / 64/60 / 82 / 96 / 96/1 / 96/100 / 96/2 / Adenocarcinoma - drug therapy / Adenocarcinoma - genetics / Adenocarcinoma - metabolism / Adenocarcinoma - pathology / Aged / Animals / Antibodies / Antineoplastic Agents - pharmacology / Apoptosis - drug effects / Biochemistry / Biomarkers, Pharmacological - metabolism / Biomedical and Life Sciences / Carcinoma, Non-Small-Cell Lung - drug therapy / Carcinoma, Non-Small-Cell Lung - genetics / Carcinoma, Non-Small-Cell Lung - metabolism / Carcinoma, Non-Small-Cell Lung - pathology / Carcinoma, Squamous Cell - drug therapy / Carcinoma, Squamous Cell - genetics / Carcinoma, Squamous Cell - metabolism / Carcinoma, Squamous Cell - pathology / Cell Biology / Cell Culture / Cell Line, Tumor / Drug Evaluation, Preclinical / Erlotinib Hydrochloride - pharmacology / Female / Gene Expression Regulation, Neoplastic / Humans / Immunology / Life Sciences / Lung Neoplasms - drug therapy / Lung Neoplasms - genetics / Lung Neoplasms - metabolism / Lung Neoplasms - pathology / Male / Mice / Mice, SCID / Middle Aged / Neoplasm Staging / Neoplastic Stem Cells - drug effects / Neoplastic Stem Cells - metabolism / Neoplastic Stem Cells - pathology / Original / original-article / Phosphorylation - drug effects / Protein Kinase Inhibitors - pharmacology / Proto-Oncogene Proteins p21(ras) - genetics / Proto-Oncogene Proteins p21(ras) - metabolism / Receptor, Epidermal Growth Factor - genetics / Receptor, Epidermal Growth Factor - metabolism / Receptor, ErbB-2 - genetics / Receptor, ErbB-2 - metabolism / Signal Transduction / Tyrosine - metabolism / Xenograft Model Antitumor Assays