title: Tyr1068-phosphorylated epidermal growth factor receptor (EGFR) predicts cancer stem cell targeting by erlotinib in preclinical models of wild-type EGFR lung cancer.
abstract: 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 (EGFRtyr1068) 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 EGFRtyr1068 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 EGFRtyr1068 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, EGFRtyr1068 was associated with EGFR-sensitizing mutations in cell lines and patient tumors, with relevant diagnostic, clinical and therapeutic implications.
authors.affiliation: Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Sette
authors.affiliation: Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Salvati
authors.affiliation: Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Mottolese
authors.affiliation: Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Visca
authors.affiliation: Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Gallo
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: K
authors.initials: K
authors.lastname: Fecchi
authors.affiliation: Department of Surgical Sciences, La Sapienza University of Rome, Rome, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Pilozzi
authors.affiliation: Department of Surgical Sciences, La Sapienza University of Rome, Rome, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Duranti
authors.affiliation: 1] Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy [2] Department of Experimental Medicine, La Sapienza University of Rome, Rome, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Policicchio
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Tartaglia
authors.affiliation: Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: M
authors.identifier: 0000000238265237
authors.initials: M
authors.lastname: Milella
authors.affiliation: Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: R
authors.initials: R
authors.lastname: De Maria
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Eramo
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D054316:Biomarkers, Pharmacological / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D009367:Neoplasm Staging; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D054316:Biomarkers, Pharmacological; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D047428:Protein Kinase Inhibitors; D016283:Proto-Oncogene Proteins p21(ras); D018719:Erb-b2 Receptor Tyrosine Kinases; D014443:Tyrosine; C117307:KRAS protein, human; C512478:EGFR protein, human; C508053:ERBB2 protein, human